EP0883402A1 - Nouveaux imidazoles cycloalkyle-substitues - Google Patents
Nouveaux imidazoles cycloalkyle-substituesInfo
- Publication number
- EP0883402A1 EP0883402A1 EP97904766A EP97904766A EP0883402A1 EP 0883402 A1 EP0883402 A1 EP 0883402A1 EP 97904766 A EP97904766 A EP 97904766A EP 97904766 A EP97904766 A EP 97904766A EP 0883402 A1 EP0883402 A1 EP 0883402A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- formula
- compound
- substituted
- optionally substituted
- 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- Withdrawn
Links
Classifications
-
- 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
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs.
- IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD1 lb/CD 18) on neutrophils without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. Conditions associated with an increased in IL-8 production (which is responsible for chemotaxis of neutrophil into the inflammatory site) would benefit by compounds which are suppressive of IL-8 production.
- Re is hydrogen, Ci-6 alkyl, C3.7 cycloalkyl, aryl, arylCi_4 alkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclyl, or heterocyclylCi-4alkyl C1-4 alkyl;
- R2 is an optionally substituted C3-7 cycloalkyl, or C3.7cycloalkylC1.10 alkyl;
- R3 is heterocyclyl, heterocyclylCi-io alkyl or Rs;
- R5 is hydrogen, -4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties
- R21 is H or alkyl 1 -6.
- R 1 ' and R ⁇ ' are independently the optional substitutents indicated above for R2-
- cycloalkyl is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
- cycloalkenyl is used herein to mean cyclic radicals, preferably of 5 to
- aralkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean Ci-4 alkyl as defined above attached to an aryl, heteroaryl or heterocyclic moiety as also defined herein unless otherwise indicate.
- an organometallic synthetic equivalent of an anion of one component is coupled with a reactive derivative of the second component, in the presence of a suitable catalyst.
- the anion equivalent may be formed from either the imidazole of Formula (IX), in which case the aryl/heteroaryl compound provides the reactive derivative, or the aryl/heteroaryl compound in which case the imidazole provides the reactive derivative.
- the compounds of formula (V ⁇ )-Scheme I may be prepared by reacting a compound of the formula (VILI)-Scheme I, R4CH2NH2 with an alkyl formate (e.g. ethylformate) to yield an intermediate amide which can be converted to the desired isonitrile by reacting with well known dehydrating agent, such as but not limited to oxalyl chloride, phosphorus oxychloride or tosyl chloride in the presence of a suitable base such as triethylamine.
- an alkyl formate e.g. ethylformate
- dehydrating agent such as but not limited to oxalyl chloride, phosphorus oxychloride or tosyl chloride in the presence of a suitable base such as triethylamine.
- this invention relates to a method of treating a mammal afflicted with a human immunodeficiency virus (HLV) which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
- HBV human immunodeficiency virus
- Compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than in humans, in need of inhibition of TNF production.
- TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
- TNF- ⁇ and TNF- ⁇ are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF” unless specifically delineated otherwise.
- a new member of the MAP kinase family alternatively termed CSBP, p38, or RK, has been identified independently by several laboratories recently. Activation of this novel protein kinase via dual phosphorylation has been observed in different cell systems upon stimulation by a wide spectrum of stimuli, such as physicochemical stress and treatment with lipopolysaccharide or proinflammatory cytokines such as interleukin- 1 and tumor necrosis factor.
- the cytokine biosynthesis inhibitors have been determined to be potent and selective inhibitors of CSBP/p38/RK kinase activity. These inhibitors are of aid in determining the signalling pathways involvement in inflammatory responses. In particular, for the first time a definitive signal transduction pathway can be prescribed to the action of lipopolysaccharide in cytokine production in macrophages.
- the cytokine inhibitors were subsequently tested in a number of animal models for anti-inflammatory activity. Model systems were chosen that were relatively insensitive to cyclooxygenase inhibitors in order to reveal the unique activities of cytokine suppressive agents. The inhibitors exhibited significant activity in many such in vivo studies.
- the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
- the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the Formulation and not deleterious to the recipient thereof.
- the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
- the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about lg.
- the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
- 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.
- Creams, ointments or pastes according to the present invention are semi-solid
- IL-1 and TNF inhibitory activity does not seem to correlate with the property of the compounds of Formula (I) in mediating arachidonic acid metabolism inhibition. Further the ability to inhibit production of prostaglandin and/or leukotriene synthesis, by nonsteroidal anti-inflammatory drugs with potent cyclooxygenase and/or lipoxygenase inhibitory activity does not mean that the compound will necessarily also inhibit TNF or LL- 1 production, at non-toxic doses.
- the cells were lysed in lOO ⁇ l of cold lysis buffer(50mM Tris/HCl pH 7.5, 150mM NaCl, 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS, 300ug/ml DNAse, 0.1% TRITON X-100, ImM PMSF, ImM leupeptin, ImM pepstatin).
- the lysate was centrifuged ( 10,000 X g for 10 min. at 4°C) to remove debris and the soluble fraction was subjected to SDS PAGE, analysis (12% gel). Protein separated on the gel were transferred onto nitrocellulose membrane by electrophoretic means for 2 hours at 60 volts.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1018996P | 1996-01-11 | 1996-01-11 | |
US10189P | 1996-01-11 | ||
PCT/US1997/000614 WO1997025047A1 (fr) | 1996-01-11 | 1997-01-10 | Nouveaux imidazoles cycloalkyle-substitues |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0883402A1 true EP0883402A1 (fr) | 1998-12-16 |
EP0883402A4 EP0883402A4 (fr) | 1999-08-11 |
Family
ID=21744400
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97904766A Withdrawn EP0883402A4 (fr) | 1996-01-11 | 1997-01-10 | Nouveaux imidazoles cycloalkyle-substitues |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0883402A4 (fr) |
JP (1) | JP2001508395A (fr) |
WO (1) | WO1997025047A1 (fr) |
Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5916891A (en) | 1992-01-13 | 1999-06-29 | Smithkline Beecham Corporation | Pyrimidinyl imidazoles |
US6512121B2 (en) | 1998-09-14 | 2003-01-28 | G.D. Searle & Co. | Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
ZA9610687B (en) * | 1995-12-22 | 1997-09-29 | Smithkline Beecham Corp | Novel synthesis. |
US5756499A (en) * | 1996-01-11 | 1998-05-26 | Smithkline Beecham Corporation | Substituted imidazole compounds |
AP9700912A0 (en) | 1996-01-11 | 1997-01-31 | Smithkline Beecham Corp | Novel cycloalkyl substituted imidazoles |
US6046208A (en) * | 1996-01-11 | 2000-04-04 | Smithkline Beecham Corporation | Substituted imidazole compounds |
JP2000507558A (ja) * | 1996-03-25 | 2000-06-20 | スミスクライン・ビーチャム・コーポレイション | Cns損傷についての新規な治療 |
WO1998007425A1 (fr) | 1996-08-21 | 1998-02-26 | Smithkline Beecham Corporation | Composes d'imidazole, compositions les contenant et leur utilisation |
US5929076A (en) * | 1997-01-10 | 1999-07-27 | Smithkline Beecham Corporation | Cycloalkyl substituted imidazoles |
EP1019394A1 (fr) | 1997-05-22 | 2000-07-19 | G.D. Searle & Co. | DERIVES DE PYRAZOLE COMME INHIBITEURS DE KINASE p38 |
US6979686B1 (en) | 2001-12-07 | 2005-12-27 | Pharmacia Corporation | Substituted pyrazoles as p38 kinase inhibitors |
US6514977B1 (en) | 1997-05-22 | 2003-02-04 | G.D. Searle & Company | Substituted pyrazoles as p38 kinase inhibitors |
US20020156104A1 (en) | 1997-06-13 | 2002-10-24 | Jerry L. Adams | Novel pyrazole and pyrazoline substituted compounds |
WO1998057966A1 (fr) | 1997-06-19 | 1998-12-23 | Smithkline Beecham Corporation | Nouveaux composes imidazole a substitution d'aryloxypymiridine |
US7301021B2 (en) | 1997-07-02 | 2007-11-27 | Smithkline Beecham Corporation | Substituted imidazole compounds |
US6489325B1 (en) | 1998-07-01 | 2002-12-03 | Smithkline Beecham Corporation | Substituted imidazole compounds |
WO1999001452A1 (fr) | 1997-07-02 | 1999-01-14 | Smithkline Beecham Corporation | Nouveaux imidazoles cycloalkyle-substitues |
TW517055B (en) | 1997-07-02 | 2003-01-11 | Smithkline Beecham Corp | Novel substituted imidazole compounds |
US6562832B1 (en) | 1997-07-02 | 2003-05-13 | Smithkline Beecham Corporation | Substituted imidazole compounds |
PT1021404E (pt) * | 1997-10-07 | 2003-04-30 | Boehringer Ingelheim Ca Ltd | Derivados de azetidinona para o tratamento de infeccoes pelo hcmv |
WO1999032121A1 (fr) | 1997-12-19 | 1999-07-01 | Smithkline Beecham Corporation | .0mposes d'imidazole heteroaryle substitues, leurs compositions et usages pharmaceutiques |
HUP0102058A3 (en) | 1998-05-22 | 2002-05-28 | Smithkline Beecham Corp | Novel 2-alkyl substituted imidazole compounds, process for their preparation, pharmaceutical compositions containing them and their use |
US6858617B2 (en) | 1998-05-26 | 2005-02-22 | Smithkline Beecham Corporation | Substituted imidazole compounds |
EP1112070B1 (fr) | 1998-08-20 | 2004-05-12 | Smithkline Beecham Corporation | Nouveaux composes de triazole substitues |
DE69914357T2 (de) | 1998-11-04 | 2004-11-11 | Smithkline Beecham Corp. | Pyridin-4-yl oder pyrimidin-4-yl substituierte pyrazine |
US6239279B1 (en) | 1998-12-16 | 2001-05-29 | Smithkline Beecham Corporation | Synthesis for 4-aryl-5-pyrimidine imidazole substituted derivatives |
US6930101B1 (en) | 1999-05-17 | 2005-08-16 | The Regents Of The University Of California | Thiazolopyrimidines useful as TNFα inhibitors |
JP2003514900A (ja) | 1999-11-23 | 2003-04-22 | スミスクライン・ビーチャム・コーポレイション | CSBP/p38キナーゼ阻害剤としての3,4−ジヒドロ−(1H)−キナゾリン−2−オン化合物 |
WO2001038313A1 (fr) | 1999-11-23 | 2001-05-31 | Smithkline Beecham Corporation | Composes de 3,4-dihydro-(1h)quinazolin-2-one comme inhibiteurs de csbp/p38 kinase |
US6759410B1 (en) | 1999-11-23 | 2004-07-06 | Smithline Beecham Corporation | 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors |
US7235551B2 (en) | 2000-03-02 | 2007-06-26 | Smithkline Beecham Corporation | 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases |
US6673818B2 (en) | 2001-04-20 | 2004-01-06 | Pharmacia Corporation | Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation |
US20030225089A1 (en) * | 2002-04-10 | 2003-12-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and p38 kinase inhibitors |
EP1707205A2 (fr) | 2002-07-09 | 2006-10-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | Compositions pharmaceutiques contenant un antichlinergique et un inhibiteur du p38 pour le traitement de maladies respiratoires |
US20060035893A1 (en) | 2004-08-07 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders |
PE20060777A1 (es) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
AT502258B1 (de) * | 2005-07-22 | 2007-09-15 | Univ Wien | Cox-i-inhibitorverbindungen |
EP1992344A1 (fr) | 2007-05-18 | 2008-11-19 | Institut Curie | P38 alpha comme cible therapeutique pour les maladies associées á une mutation de FGFR3 |
US20120245188A1 (en) * | 2010-11-15 | 2012-09-27 | Translational Genomics Research Institute | Methods of treating memory loss and enhancing memory performance |
US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
WO2019071147A1 (fr) | 2017-10-05 | 2019-04-11 | Fulcrum Therapeutics, Inc. | Inhibiteurs de la kinase p38 réduisant l'expression du gène dux4 et des gènes aval pour le traitement de la fshd |
CA3209491A1 (fr) | 2021-03-15 | 2022-09-22 | Saul Yedgar | Dipalmitoyl-phosphatidyl-ethanol-amine conjuguee a l'acide hyaluronique en combinaison avec des medicaments anti-inflammatoires non steroidiens (ains) pour traiter ou soulager des maladies inflammatoire |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995002591A1 (fr) * | 1993-07-16 | 1995-01-26 | Smithkline Beecham Corporation | Imidazoles a tri-substitution et proprietes therapeutiques multiples |
WO1996021654A1 (fr) * | 1995-01-12 | 1996-07-18 | Smithkline Beecham Corporation | Nouveaux composes |
-
1997
- 1997-01-10 WO PCT/US1997/000614 patent/WO1997025047A1/fr not_active Application Discontinuation
- 1997-01-10 JP JP52546597A patent/JP2001508395A/ja active Pending
- 1997-01-10 EP EP97904766A patent/EP0883402A4/fr not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995002591A1 (fr) * | 1993-07-16 | 1995-01-26 | Smithkline Beecham Corporation | Imidazoles a tri-substitution et proprietes therapeutiques multiples |
WO1996021654A1 (fr) * | 1995-01-12 | 1996-07-18 | Smithkline Beecham Corporation | Nouveaux composes |
Non-Patent Citations (1)
Title |
---|
See also references of WO9725047A1 * |
Also Published As
Publication number | Publication date |
---|---|
JP2001508395A (ja) | 2001-06-26 |
EP0883402A4 (fr) | 1999-08-11 |
WO1997025047A1 (fr) | 1997-07-17 |
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Legal Events
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
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