WO1999061440A1 - Nouveaux composes d'imidazole substitue - Google Patents

Nouveaux composes d'imidazole substitue Download PDF

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WO1999061440A1
WO1999061440A1 PCT/US1999/011455 US9911455W WO9961440A1 WO 1999061440 A1 WO1999061440 A1 WO 1999061440A1 US 9911455 W US9911455 W US 9911455W WO 9961440 A1 WO9961440 A1 WO 9961440A1
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alkyl
heterocyclic
hydrogen
disease
formula
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PCT/US1999/011455
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Jerry Leroy Adams
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Smithkline Beecham Corporation
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Priority to EP99924480A priority Critical patent/EP1082320A4/fr
Priority to CA002333157A priority patent/CA2333157A1/fr
Priority to JP2000550846A priority patent/JP2002516325A/ja
Publication of WO1999061440A1 publication Critical patent/WO1999061440A1/fr

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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
    • C07D401/14—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/00—Drugs for skeletal disorders
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    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
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    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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

Definitions

  • This invention relates to a novel group of imidazole compounds, processes for the preparation thereof, the use thereof in treating ERK/MAP mediated diseases and pharmaceutical compositions for use in such therapy.
  • This invention relates to the novel compounds of Formula (I) and pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable diluent or carrier.
  • This invention relates to a method of treating a ERK/MAP kinase mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • This invention also relates to a method of inhibiting the ERK/MAP kinase in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • Rl is hydrogen, Ci-5 alkyl, halogen, Ci-5 alkoxy, or arylCi-5 alkyl;
  • R2 is hydrogen, Ci-5 alkyl, aryl, arylCi-5 alkyl, heteroaryl, heteroarylC ⁇ .5 alkyl, heterocyclic, heterocyclic Cj_5 alkyl;
  • R3 is hydrogen, or C 1.3 alkyl
  • R4 is hydrogen, Ci-5 alkyl, aryl, arylCi-5 alkyl, heteroaryl, heteroarylCi ..5 alkyl, heterocyclic, heterocyclic C ⁇ .5 alkyl; or a pharmaceutically acceptable salt thereof.
  • suitable Ri moieties include hydrogen, Ci .5 alkyl, halogen, C1-.5 alkoxy or arylCi-5 alkyl.
  • the moiety is a Ci .5 alkyl, which may be branched or unbranched.
  • R2 is hydrogen, Ci-5 alkyl, aryl, arylCi-5 alkyl, heteroaryl, heteroarylCi.5 alkyl, heterocyclic, heterocyclic C ⁇ _5 alkyl, wherein all of these moieties may be optionally substituted as defined below.
  • the heterocyclic ring is a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N,
  • O, or S such as, but not limited to pyrrolindinyl, piperidine, morpholino, tetra- hydropyran, tetrahydrothiopyranyl, tetrahydrothipyransulfinyl, tetrahydro- thiopyransulfonyl, pyrrolindinyl, or an indole ring.
  • R2 is a heteroaryl or heteroarylalkyl moiety
  • the heteroaryl portion is a
  • 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, tetrazole, triazole, imidazole, or benzimidazole.
  • R3 is hydrogen, or Ci .3 alkyl (branched or unbranched).
  • R4 is hydrogen, Ci-5 alkyl, aryl, arylCi-5 alkyl, heteroaryl, heteroarylCi .5 alkyl, heterocyclic, heterocyclic C1.5 alkyl, and wherein all of these moieties may be optionally substituted as defined below.
  • Suitable heteroaryl and heterocyclic containing moieties for use herein are the same as those described above for R 2 .
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy such as methoxy or ethoxy
  • halosubstituted Ci-io alkoxy such as methoxy or ethoxy
  • S(O)m alkyl such as methyl thio, methylsulfinyl or methyl sulfonyl
  • amino, mono & di-C ⁇ .5 alkyl substituted amino such as the moiety R7R17 wherein R7 and Ri 7 are hydrogen or C 1.5 alkyl, or where the R7 and Ri 7 substituent groups may together with the nitrogen to which they are attached cyclize to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O N/S; Ci-io alkyl, C3_7 cycloalkyl, or
  • Ci -i 0 alkyl group such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; halosubstituted Ci-io alkyl, such CF2CF2H, or CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl moieties may also be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Ci-io alkoxy; S(O)malkyl; amino, mono & di-substituted amino, such as in the NR7R17 group; alkyl, or CF3.
  • Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.
  • pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety.
  • Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
  • halo or halogens
  • halogens include the halogens: chloro, fluoro, bromo and iodo.
  • C ⁇ _5alkyl or “alkyl” - includes both straight and branched chain radicals of 1 to 5 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, r ⁇ -propyl, iso-p ⁇ opy ⁇ , «-butyl, sec-butyl, tsobutyl, tert-butyl, «-pentyl and the like.
  • 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. • "aryl” - phenyl and naphthyl;
  • heteroaryl (on its own or in any combination, such as “heteroaryloxy”, or “heteroaryl alkyl”) - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, tetrazole, triazole, imidazole, or benzimidazole.
  • heterocyclic (on its own or in any combination, such as
  • heterocyclylalkyl a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
  • 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.
  • the compounds of the present invention may exist as stereoisomers, regioisomers, or diastereiomers. These compounds may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are included within the scope of the present invention.
  • Exemplified compounds of Formula (I) include: l-(4-Piperidinyl)-4-methyl-5-(3-amino-pyrimidin-4-yl)imidazole; or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula (I) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes herein.
  • the synthesis provided for in these Schemes is applicable for the producing compounds of Formula (I) having a variety of different Ri , R2, R3,and R4 groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed.
  • Suitable protecting groups for use with the imidazole nitrogen are well known in the art and described in many references, for instance, Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981.
  • an example of an imidazole nitrogen protecting group is tetrahydropyranyl.
  • Isolation of 3 may not be required as under the dehydrating conditions described for the formylation of 2, cyclodehydration to form the intermediate munchnone may occur.
  • Reaction of the thus formed munchnone with a sulfonylimine (formed by condensation of the sulfonamide with R2COH) provides the imidazole cycloaddition adduct, 4.
  • the general procedures for this chemistry and the specific application for the formation of imidazoles are described in Consonni, R. et. al. J.Chem. Research (S) pi 88
  • 2-thioalkylpyrimidine to the more activated sulfoxide and/or sulfone leaving group allows facile displacement of the sulfur with a variety of nucleophiles, including ammonia and simple alkyl amines (R3), to afford the desired 2-aminopyrimindines, 5.
  • the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of an ERK kinase mediated disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated ERK2/MAP kinase activation by such mammal's cell, such as but not limited to monocytes and/or macrophages.
  • Intracellular signal transduction is the means by which cells respond to extracellular stimuli. Regardless of the nature of the cell surface receptor (e. g. protein tyrosine kinase or seven-transmembrane G-protein coupled), protein kinases and phosphatases along with phopholipases are the essential machinery by which the signal is further transmitted within the cell [Marshall, J.C. Cell , 80, 179-278 (1995)].
  • the cell surface receptor e. g. protein tyrosine kinase or seven-transmembrane G-protein coupled
  • protein kinases and phosphatases along with phopholipases are the essential machinery by which the signal is further transmitted within the cell [Marshall, J.C. Cell , 80, 179-278 (1995)].
  • Protein kinases can be categorized into five classes with the two major classes being, tyrosine kinases and serine / threonine kinases depending upon whether the enzyme phosphorylates its substrate(s) on specific tyrosine(s) or serine / threonine(s) residues [Hunter, T. Methods in Enzymology (Protein Kinase Classification) p. 3, Hunter, T.; Sefton, B. M.; eds. vol. 200, Academic Press; San Diego, 1991].
  • MAP kinase or ERK (extracellular signal regulated kinase) family is a novel set of kinases which are intimately involved with and in many cases required for the intracellular transmission of mitogenic or growth signals.
  • ERK1 and ERK2 were the first two members of the family to be identified.
  • a characteristic requirement for activation of these kinases is the dual phosphorylation on the TEY sequence of the kinase activation loop, a reaction which is effected by a select group of upstream kinases, know as MAP kinase kinases (MAPKK).
  • the JNK and p38 kinases constitute two additional arms of the MAP kinase pathway which are primarily activated by "stress" signals. All three pathways are independent and are composed of additional family members. Although independent there is considerable crosstalk between the pathways and in most cases an extracellular signal will activate several parts of the pathway; hence is the unique pattern and strength of the signals which emerge from these kinase cascades which will influence the cellular response.
  • the different MAP family members are distinguished by the identify of the dual activation sequence.
  • the JNK kinases contain TPY and the p38 kinases TGY, whereas as noted earlier the ERK kinases contain TEY.
  • the compounds of Formula (I) may also be used topically in the treatment or prophylaxis of topical disease states mediated by or exacerbated by excessive
  • ERK/MAP kinase production such as inflamed joints, eczema, psoriasis and other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis, pyresis, pain and other conditions associated with inflammation.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit ERK/MAP activity such that it is regulated down to normal levels, or in some case to subnormal levels, so as to ameliorate or prevent the disease state.
  • the term "inhibiting the activity ERK/MAP kinase refers to: a) a decrease of excessive in vivo levels of the kinase in a human to normal or sub-normal levels by inhibition of the in vivo release of the kinase by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the genomic level, of excessive in vivo levels of the kinase in a human to normal or sub-normal levels; c) a down regulation, by inhibition of the direct synthesis of the kinase as a postranslational event; or d) a down regulation, at the translational level, of excessive in vivo levels of the kinase in a human to normal or sub-normal levels.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof in therapy it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
  • This invention also relates to a pharmaceutical composition comprising an effective, non- toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
  • Compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation.
  • the compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures.
  • the compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • 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 pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl mono- stearate or glyceryl distearate alone or with a wax.
  • 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 25mg. 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.
  • Compounds of Formula (I) may be administered topically, that is by non- systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation.
  • 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 formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting- solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C. for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Compounds of Formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the daily oral dosage regimen will preferably be from about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 0.5 mg to 15mg.
  • the daily parenteral dosage regimen about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from about 0.5 mg to 15mg/kg.
  • the daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily.
  • the daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • novel compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of ERK/MAP kinase inhibition or production.
  • ERK/MAP inhibiting effects of compounds of the present invention are determined by the following in vitro assay:
  • the ERK kinase assay was performed using a commercially available kit (P44MPK Upstate Biotechnology Inc.) Kinase activity was determined by measuring the incorporation of 2 from ⁇ -[32p]ATP into an EGFR-derived peptide (T669) having the following sequence: KRELVEPLTPSGEAPNQALLR. Reactions (30 ⁇ l) contained 25 mM Hepes buffer, pH 7.4, 8 mM MgCl 2 ; 10 ⁇ M Na-vanadate; 1 mM EDTA, 0.8 ⁇ Ci/170 ⁇ M
  • the title compound can be prepared by the synthetic route illustrated in Scheme 2 using the reaction conditions described in Consonni, R. et. al. J.Chem. Research (S) pl88 (1991) and Croce, P.D., et. al.. J. Heterocyclic Chem. 24, 1793 (1987) or modifications thereof which are apparent to one skilled in the art of organic synthesis.
  • the synthesis of the requisite starting pyrimidine aldehyde and the t-Boc- 4-aminopiperidine are described in US Patent 5,670,527 whose disclosure is incorporated herein by reference in its entirety.

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Abstract

L'invention concerne de nouveaux composés d'imidazole 1,4,5-substitué et des compositions destinées à être utilisées comme inhibiteurs d'ERK/MAP dans des affections induites par ERK/MAP.
PCT/US1999/011455 1998-05-26 1999-05-25 Nouveaux composes d'imidazole substitue WO1999061440A1 (fr)

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EP99924480A EP1082320A4 (fr) 1998-05-26 1999-05-25 Nouveaux composes d'imidazole substitue
CA002333157A CA2333157A1 (fr) 1998-05-26 1999-05-25 Nouveaux composes d'imidazole substitue
JP2000550846A JP2002516325A (ja) 1998-05-26 1999-05-25 新規な置換イミダゾール化合物

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WO2000035436A2 (fr) * 1998-12-16 2000-06-22 Warner-Lambert Company Traitement de l'arthrite a l'aide d'inhibiteurs de la mek
WO2002022610A1 (fr) * 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Soxazoles et leur utilisation comme inhibiteur d'erk
US6362193B1 (en) 1997-10-08 2002-03-26 Smithkline Beecham Corporation Cycloalkenyl substituted compounds
US6489325B1 (en) 1998-07-01 2002-12-03 Smithkline Beecham Corporation Substituted imidazole compounds
US6562832B1 (en) 1997-07-02 2003-05-13 Smithkline Beecham Corporation Substituted imidazole compounds
US6599910B1 (en) 1998-08-20 2003-07-29 Smithkline Beecham Corporation Substituted triazole compounds
US6610695B1 (en) 1997-06-19 2003-08-26 Smithkline Beecham Corporation Aryloxy substituted pyrimidine imidazole compounds
US6664395B2 (en) 2001-04-04 2003-12-16 Pfizer Inc Benzotriazoles anti-inflammatory compounds
US6696464B2 (en) 2001-03-09 2004-02-24 Pfizer Inc Triazolo-pyridines anti-inflammatory compounds
US6774127B2 (en) 1997-06-13 2004-08-10 Smithkline Beecham Corporation Pyrazole and pyrazoline substituted compounds
EP1539121A2 (fr) * 2002-08-29 2005-06-15 Scios Inc. Methode pour favoriser l'osteogenese
US6949652B2 (en) 2002-08-30 2005-09-27 Pfizer, Inc. Crystalline forms of 3-isopropyl-6-[4-(2,5-difluoro-phenyl)-oxazol-5-yl]-[1,2,4]triazolo-[4,3-A]pyridine
US7005523B2 (en) 2002-08-30 2006-02-28 Pfizer Inc. Cycloalkyl-[4-(trifluorophenyl)-oxazol-5yl]-triazolo-pyridines
US7012143B2 (en) 2002-08-30 2006-03-14 Dombroski Mark A Cycloalkyl-[4-(difluorophenyl)-oxazol-5-yl]-triazolo-pyridines
US7037923B2 (en) 2002-08-30 2006-05-02 Pfizer, Inc. Alkyl-[4-(trifluorophenyl)-oxazol-5-yl]-triazolo-pyridines
WO2006050249A1 (fr) * 2004-10-29 2006-05-11 Vertex Pharmaceuticals Incorporated Derives de diaminotriazole utilises comme inhibiteurs de proteine kinases
US7053099B1 (en) 1999-11-23 2006-05-30 Smithkline Beecham Corporation 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors
US7056918B2 (en) 2001-03-09 2006-06-06 Pfizer, Inc. Benzimidazole anti-inflammatory compounds
EP1676574A2 (fr) 2004-12-30 2006-07-05 Johnson & Johnson Vision Care, Inc. Procédé favorisant la survie des tissus ou cellules griffées
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
US7244441B2 (en) 2003-09-25 2007-07-17 Scios, Inc. Stents and intra-luminal prostheses containing map kinase inhibitors
US7259171B2 (en) 2002-08-30 2007-08-21 Pfizer Inc. Di and trifluoro-triazolo-pyridines anti-inflammatory compounds
US7301021B2 (en) 1997-07-02 2007-11-27 Smithkline Beecham Corporation Substituted imidazole compounds
WO2008142031A1 (fr) 2007-05-18 2008-11-27 Institut Curie La p38alpha cible thérapeutique dans le cancer de la vessie
EP2116245A2 (fr) 2004-08-07 2009-11-11 Boehringer Ingelheim International GmbH combinaisons d'inhibiteurs de la kinase EGFR pour le traitement de désordres respiratoires et de l'appareil digestif
EP2384751A1 (fr) 2004-12-24 2011-11-09 Boehringer Ingelheim International Gmbh Médicaments pour le traitement ou la prévention des maladies fibrogènes
US8512695B2 (en) 2008-10-21 2013-08-20 The General Hospital Corporation Method of preventing fat graft resorption by administering fat-derived cells and poloxamer P 188
US10184110B2 (en) 2010-08-06 2019-01-22 The General Hospital Corporation System and apparatus for cell treatment
WO2020192750A1 (fr) 2019-03-28 2020-10-01 江苏恒瑞医药股份有限公司 Dérivé thiénohétérocyclique, son procédé de préparation et son utilisation médicale
WO2020200069A1 (fr) 2019-03-29 2020-10-08 江苏恒瑞医药股份有限公司 Dérivé pyrrolohétérocyclique, son procédé de préparation et son application en médecine
WO2020238776A1 (fr) 2019-05-24 2020-12-03 江苏恒瑞医药股份有限公司 Dérivé bicyclicque condensé substituté, son procédé de préparation et son application en médecine
WO2022068860A1 (fr) 2020-09-29 2022-04-07 江苏恒瑞医药股份有限公司 Forme cristalline d'un dérivé pyrrolo-hétérocyclique et son procédé de préparation

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ATE429250T1 (de) * 2003-02-26 2009-05-15 Kowa Co Mittel zur behandlung der allergischen kontaktdermatitis
AU2010231514A1 (en) * 2009-04-01 2011-11-03 Rappaport Family Institute For Research In The Medical Sciences A method of regulating proliferation and differentiation of keratinocytes

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AU5147598A (en) * 1996-10-17 1998-05-11 Smithkline Beecham Corporation Methods for reversibly inhibiting myelopoiesis in mammalian tissue

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WANG Z., ET AL.: "STRUCTURAL BASIS OF INHIBITOR SELECTIVITY IN MAP KINASES.", STRUCTURE, CURRENT BIOLOGY LTD., PHILADELPHIA, PA., US, vol. 06., no. 09., 15 September 1998 (1998-09-15), US, pages 1117 - 1128., XP002923383, ISSN: 0969-2126, DOI: 10.1016/S0969-2126(98)00113-0 *

Cited By (40)

* Cited by examiner, † Cited by third party
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US6774127B2 (en) 1997-06-13 2004-08-10 Smithkline Beecham Corporation Pyrazole and pyrazoline substituted compounds
US6610695B1 (en) 1997-06-19 2003-08-26 Smithkline Beecham Corporation Aryloxy substituted pyrimidine imidazole compounds
US7301021B2 (en) 1997-07-02 2007-11-27 Smithkline Beecham Corporation Substituted imidazole compounds
US6562832B1 (en) 1997-07-02 2003-05-13 Smithkline Beecham Corporation Substituted imidazole compounds
US6362193B1 (en) 1997-10-08 2002-03-26 Smithkline Beecham Corporation Cycloalkenyl substituted compounds
US6489325B1 (en) 1998-07-01 2002-12-03 Smithkline Beecham Corporation Substituted imidazole compounds
US6599910B1 (en) 1998-08-20 2003-07-29 Smithkline Beecham Corporation Substituted triazole compounds
WO2000035436A2 (fr) * 1998-12-16 2000-06-22 Warner-Lambert Company Traitement de l'arthrite a l'aide d'inhibiteurs de la mek
WO2000035436A3 (fr) * 1998-12-16 2001-10-18 Warner Lambert Co Traitement de l'arthrite a l'aide d'inhibiteurs de la mek
US7053099B1 (en) 1999-11-23 2006-05-30 Smithkline Beecham Corporation 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors
US6649640B2 (en) 2000-09-15 2003-11-18 Vertex Pharmaceuticals Incorporated Isoxazole compositions useful as inhibitors of ERK
WO2002022610A1 (fr) * 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Soxazoles et leur utilisation comme inhibiteur d'erk
US7354919B2 (en) 2000-09-15 2008-04-08 Vertex Pharmaceuticals Incorporated Isoxazole compositions useful as inhibitors of ERK
US6495582B1 (en) 2000-09-15 2002-12-17 Vertex Pharmaceuticals Incorporated Isoxazole compositions useful as inhibitors of ERK
US6696464B2 (en) 2001-03-09 2004-02-24 Pfizer Inc Triazolo-pyridines anti-inflammatory compounds
US7056918B2 (en) 2001-03-09 2006-06-06 Pfizer, Inc. Benzimidazole anti-inflammatory compounds
US6664395B2 (en) 2001-04-04 2003-12-16 Pfizer Inc Benzotriazoles anti-inflammatory compounds
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
EP1539121A2 (fr) * 2002-08-29 2005-06-15 Scios Inc. Methode pour favoriser l'osteogenese
US7268139B2 (en) 2002-08-29 2007-09-11 Scios, Inc. Methods of promoting osteogenesis
EP1539121A4 (fr) * 2002-08-29 2008-08-13 Scios Inc Methode pour favoriser l'osteogenese
US7005523B2 (en) 2002-08-30 2006-02-28 Pfizer Inc. Cycloalkyl-[4-(trifluorophenyl)-oxazol-5yl]-triazolo-pyridines
US7037923B2 (en) 2002-08-30 2006-05-02 Pfizer, Inc. Alkyl-[4-(trifluorophenyl)-oxazol-5-yl]-triazolo-pyridines
US7259171B2 (en) 2002-08-30 2007-08-21 Pfizer Inc. Di and trifluoro-triazolo-pyridines anti-inflammatory compounds
US6949652B2 (en) 2002-08-30 2005-09-27 Pfizer, Inc. Crystalline forms of 3-isopropyl-6-[4-(2,5-difluoro-phenyl)-oxazol-5-yl]-[1,2,4]triazolo-[4,3-A]pyridine
US7012143B2 (en) 2002-08-30 2006-03-14 Dombroski Mark A Cycloalkyl-[4-(difluorophenyl)-oxazol-5-yl]-triazolo-pyridines
US7244441B2 (en) 2003-09-25 2007-07-17 Scios, Inc. Stents and intra-luminal prostheses containing map kinase inhibitors
EP2116245A2 (fr) 2004-08-07 2009-11-11 Boehringer Ingelheim International GmbH combinaisons d'inhibiteurs de la kinase EGFR pour le traitement de désordres respiratoires et de l'appareil digestif
WO2006050249A1 (fr) * 2004-10-29 2006-05-11 Vertex Pharmaceuticals Incorporated Derives de diaminotriazole utilises comme inhibiteurs de proteine kinases
EP2384751A1 (fr) 2004-12-24 2011-11-09 Boehringer Ingelheim International Gmbh Médicaments pour le traitement ou la prévention des maladies fibrogènes
EP2878297A1 (fr) 2004-12-24 2015-06-03 Boehringer Ingelheim International GmbH Médicaments pour le traitement ou la prévention des maladies fibrogènes
EP1676574A2 (fr) 2004-12-30 2006-07-05 Johnson & Johnson Vision Care, Inc. Procédé favorisant la survie des tissus ou cellules griffées
WO2008142031A1 (fr) 2007-05-18 2008-11-27 Institut Curie La p38alpha cible thérapeutique dans le cancer de la vessie
US8512695B2 (en) 2008-10-21 2013-08-20 The General Hospital Corporation Method of preventing fat graft resorption by administering fat-derived cells and poloxamer P 188
US9730963B2 (en) 2008-10-21 2017-08-15 The General Hospital Corporation Cell transplantation
US10184110B2 (en) 2010-08-06 2019-01-22 The General Hospital Corporation System and apparatus for cell treatment
WO2020192750A1 (fr) 2019-03-28 2020-10-01 江苏恒瑞医药股份有限公司 Dérivé thiénohétérocyclique, son procédé de préparation et son utilisation médicale
WO2020200069A1 (fr) 2019-03-29 2020-10-08 江苏恒瑞医药股份有限公司 Dérivé pyrrolohétérocyclique, son procédé de préparation et son application en médecine
WO2020238776A1 (fr) 2019-05-24 2020-12-03 江苏恒瑞医药股份有限公司 Dérivé bicyclicque condensé substituté, son procédé de préparation et son application en médecine
WO2022068860A1 (fr) 2020-09-29 2022-04-07 江苏恒瑞医药股份有限公司 Forme cristalline d'un dérivé pyrrolo-hétérocyclique et son procédé de préparation

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