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WO2006117657A1 - Derives de triazolone utilises comme agents anti-inflammatoires - Google Patents

Derives de triazolone utilises comme agents anti-inflammatoires Download PDF

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Publication number
WO2006117657A1
WO2006117657A1 PCT/IB2006/001143 IB2006001143W WO2006117657A1 WO 2006117657 A1 WO2006117657 A1 WO 2006117657A1 IB 2006001143 W IB2006001143 W IB 2006001143W WO 2006117657 A1 WO2006117657 A1 WO 2006117657A1
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Prior art keywords
compound
triazol
dihydro
fluorophenyl
pyridin
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PCT/IB2006/001143
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English (en)
Inventor
Venkata P. Palle
Ashwani Kumar Verma
Sanjay Malhotra
Abhijit Ray
Geeta Sharma
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present invention relates to novel triazolone derivatives as anti-inflammatory agents.
  • the compounds described herein can be useful for inhibition and prevention of inflammation and associated pathologies including inflammatory and autoimmune diseases such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis.
  • This invention also relates to pharmacological compositions containing compounds described herein and the methods of treating sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis, and other inflammatory and/or autoimmune disorders, using the compounds.
  • cytokines a unique class of ontracellular regulatory proteins, in the pathogenesis of many diseases.
  • Cytokines play a crucial role in initiating, maintaining, and regulating immunological and inflammatory processes.
  • Advances in our understanding of their role in immune and inflammatory disorders have led to the development of cytokine-based therapies-that is, therapies that aim to inhibit or restore the activity of specific cytokines.
  • drugs that block inflammatory cytokines such as tumor necrosis factor-alpha (TNF- ⁇ ) are among the most successful agents being introduced to the market.
  • TNF- ⁇ tumor necrosis factor-alpha
  • Elevated levels of proinflammatory cytokines viz TNF- ⁇ and IL- l ⁇ are associated with the pathogenesis of many immune mediated inflammatory disorders like sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disease, organ transplant rejection and psoriasis. Inflammation is regulated by a large number of pro- and anti-inflammatory mediators, which include cytokines, eicosanoids, nitric oxide, and reactive oxygen species. The central role of these inflammatory mediators in the pathogenesis of both chronic and acute inflammatory diseases is well documented.
  • inflammatory disorders were treated primarily with relatively non-selective anti-inflammatory agents, such as corticosteroids and various non-steroidal anti-inflammatory drugs.
  • anti-inflammatory agents such as corticosteroids and various non-steroidal anti-inflammatory drugs.
  • novel therapies have been developed that specifically interfere with the action of selected pro-inflammatory mediators, such as TNF- ⁇ and PGE-2. These specific anti-inflammatory therapies have already proven to be very successful in the treatment of rheumatoid arthritis, inflammatory bowel disease, and several other inflammatory diseases.
  • TNF- ⁇ tumor necrosis factor-alpha
  • etanercept Enbrel; Amgen/Wyeth
  • infliximab Resmicade; Centocor
  • adalimumab Humira; Abbott
  • Kineret - an interleukin-1 (IL-lbeta) receptor antagonist further indicates the clinical activity of protein-based therapies that regulate cytokine activities.
  • current injectable therapies have associated limitations and risks, including the potential for increased malignancies and infections and increased congestive heart failure.
  • p38 MAPK mitogen activated protein kinase
  • ERK extracellular regulated kinases
  • JNK c-jun N terminal kinases
  • MAP kinases are Serine Threonine Kinases that transduce environmental stimuli to the nucleus. They are activated by upstream MAPK kinases by phosphorylation on both tyrosine and threonine residues.
  • the MAPK pathways are involved in alterations in cell physiology resulting from a variety of stimuli and control cell death, cell cycle machinery, gene transcription and protein translation.
  • p38 ⁇ MAPK was first identified as a tyrosine phosphorylated protein in LPS (Lipopolysaccharide) stimulated macrophages.
  • the human p38 ⁇ MAPK was identified as the target of pyridinyl imidazole compounds (cytokine suppressive anti-inflammatory drugs) that were known to block TNF- ⁇ and IL-I release from LPS stimulated monocytes. After the cloning of first p38 MAPK (p38 ⁇ ), additional members of the p38 MAPK family were cloned by homology, including the p38 ⁇ ; p38 ⁇ and p38 ⁇ .
  • p38 pathway controls the activity of multiple transcription factors and the expression of many genes.
  • p38 inhibitors have been shown to effectively block both TNF- ⁇ and IL-I biosynthesis by LPS stimulated human monocytes, hi addition, p38 MAPK also plays a role in the production of IL-4, IL-6, IL-8 and IL-12.
  • p38 MAPK is also critical for cell response to certain cytokines. Treatment of human neutrophils with GM-CSF, TNF- ⁇ or TGF- ⁇ results in p38 activation.
  • GM-CSF and TNF- ⁇ are potent enhancers of neutrophil respiratory activity suggesting a role for p38 MAPK in respiratory burst.
  • p38 has also been implicated in the induction of cyclooxygenase-2 (COX-2) in LPS induced monocytes.
  • COX-2 enzyme is the key enzyme in the production of prostaglandins from arachidonic acid.
  • Inhibitors of p38 MAP kinase are also expected to inhibit COX-2 expression. Accordingly inhibitors of cytokine synthesis would be expected to be effective in disorders currently treated with NSAID 's. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease.
  • U.S. Patent No. 5,681,841 discloses cyclic urea derivatives, pharmaceutical compositions containing these compounds and process for preparing them.
  • U.S. Patent No. 6,528,957 discloses N-aryl-l,2,4-triazolin-5-one derivatives.
  • WO 94/11357 discloses process for the preparation of triazolone compounds.
  • WO 00/59506 discloses heterocyclic containing biphenyl derivatives said to be useful for the treatment of diabetes and related disorders and method of preparing them.
  • WO 97/03067 discloses piperazine derivatives as therapeutic agents.
  • Canadian Patent No. 2,197,789 discloses cyclic urea derivatives, pharmaceutical compositions containing these compounds and process for preparing them.
  • the present invention provides triazolone derivatives, which can be used for the inhibition and prevention of inflammation and associated pathologies such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis.
  • inflammatory and autoimmune diseases such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rej ection and psoriasis.
  • each G 1 can be selected from aryl or heteroaryl;
  • R can be alkyl, cycloalkyl, heteroaryl, heterocyclyl, aryl, cycloalkylalkyl, heterocyclylalkyl, heteroarylalkyl, or -(CH 2 ) g CONR x R y [wherein R x and R y can be independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, -SO n R 1 (wherein n is 0, 1 or 2), heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl (wherein R 1 can be hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl)]; and g is an integer selected from 1-3;
  • a method for the treatment of mammal suffering from inflammation and associated pathologies in accordance with second aspect, there is provided a method for the treatment of mammal suffering from inflammation and associated pathologies.
  • a method for the treatment of mammal suffering from inflammatory diseases and associated pathologies including sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis.
  • compositions containing the compounds and which may also contain pharmaceutically acceptable carriers or diluents, which may be used for the treatment of inflammatory and autoimmune diseases such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis.
  • inflammatory and autoimmune diseases such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis.
  • inflammatory and autoimmune diseases such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis.
  • a process for the preparation of compounds disclosed herein there is provided a process for the preparation of compounds disclosed herein.
  • the compounds described herein may be screened as p38 MAP Kinas
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms.
  • Alkyl groups can be optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, a phenylene, sulphinyl, sulphonyl group or -NR a -, wherein R a can be hydrogen, alkyl, alkenyl, alkynyl cycloalkyl or aryl.
  • This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or geminal geometry. It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and - NR a - 5 wherein R a can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NRa-, wherein R a can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom.
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefmic bonds, unless otherwise constrained by the definition.
  • Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including adamantanyl, tricyclo[3.3.1.1 ]decane, bicyclo[2.2.2]octane, bicyclo[4.4.0]decane, bicylco[4.3.0]nonane, bicyclo[3.3.0]octane, bicyclo [2.2.1] heptane and the like, or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like.
  • alkoxy denotes the group O-alkyl, wherein alkyl is the same as defined above.
  • aryl herein refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups.
  • the aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
  • a cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
  • Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
  • aralkyl refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined below.
  • alkyl groups include benzyl, ethylphenyl, propylphenyl, naphthylmethyl and the like.
  • alkenyl refers to alkenyl-aryl linked through alkenyl (wherein alkenyl is as defined above) portion and the alkenyl portion contains 1 to 6 carbon atoms and aryl is as defined below.
  • aryloxy denotes the group O-aryl, wherein aryl is as defined above.
  • heteroaryl refers to an aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic or tricyclic aromatic group having from 8 to 14 ring atoms, with one or more heteroatom(s) independently selected from N, O or S.
  • the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring.
  • heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzo turanyl, indolyl, benzothiazolyl, or benzoxazolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl,
  • Such ring systems can be mono-, bi- or tricyclic. Carbonyl or sulfonyl group can replace carbon atom(s) of heterocyclyl. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s).
  • heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl, benzimidazolyl, tetrazolyl, carbaxolyl, indolyl, phenoxazinyl, phenothiazinyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piperazinyl, 3H-imidazo[4,5-b]pyridine, isoquinolinyl, lH-pyrrolo[2,3- b]pyridine, and the like.
  • Heteroarylalkyl refers to alkyl-heteroaryl group linked tlirough alkyl portion, wherein the alkyl and heteroaryl are as defined earlier.
  • Heterocyclylalkyl refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are as defined earlier.
  • leaving group refers to groups that exhibit or potentially exhibit the properties of being labile under the synthetic conditions and also, of being readily separated from synthetic products under defined conditions.
  • leaving groups include, but are not limited to, halogen (e.g., F, Cl, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, or hydroxy radicals and the like.
  • protecting groups refers to moieties that prevent chemical reaction at a location of a molecule intended to be left unaffected during chemical modification of such molecule. Unless otherwise specified, protecting groups may be used on groups, such as hydroxy, amino, or carboxy. Examples of protecting groups are found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2 nd Ed., John Wiley and Sons, New York, N. Y., which is incorporated herein by reference. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups employed are not critical, as long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.
  • pharmaceutically acceptable salts refers to derivatives of compounds that can be modified by forming their corresponding acid or base salts.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts of basic residues (such as amines), or alkali or organic salts of acidic residues (such as carboxylic acids), and the like.
  • cycloalkenyl refers to unsaturated carbocyclic ring having three to seven carbon atoms.
  • One or more hydrogen of said alkenyl or alkynyl can be replaced by halogen, hydroxy, cyano, or -NR 44 R 55 , wherein R 44 and R 55 are selected from hydrogen and alkyl.
  • Examples of cycloalkenyl include, but are not limited to, cyclopropenyl and cyclobutenyl, and the like. Multiple cyclic structures are also included.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • solvates refers to solvates with water (i.e., hydrates, hemihydrate or sesquihydrate) or pharmaceutically acceptable solvents, for example solvates with common organic solvents as ethanol and the like. Such solvates are also encompassed within the scope of the disclosure.
  • alkylene refers to a diradical of the branched or unbranched saturated hydrocarbon chain as defined above for the term “alkyl.” This term is exemplified by groups such as methylene, ethylene, propylene isomers (e.g., -CH 2 CH 2 CH 2 and -CH(CH 3 )CH 2 ) and the like.
  • alkenylene refers to a diradical of a branched or unbranched unsaturated hydrocarbon group as defined above for the term “alkenyl.” hi the event that alkenylene is attached to the heteroatom, the double bond cannot be alpha to the heteroatom. Alkenylene groups are connected by two bonds to the rest of the structure of compound of Formula I.
  • the compounds described herein may be prepared by techniques well known in the art and familiar to a practitioner skilled in art of this invention.
  • the compounds of the present invention may be prepared by the processes described herein, those processes are not the only means by which the compounds described may be synthesised. Further, the various synthetic steps described herein may be performed in an alternate sequence in order to give the desired compounds.
  • the compounds of Formulae IV and V can be prepared by, for example, following the procedure as depicted in Scheme I.
  • a compound of Formula II (G 1 is the same as defined earlier) can be reacted with a compound of Formula III [hal is Cl, Br or I and P 1 is aryl (such as phenyl or p-nitrophenyl)] to give a compound of Formula FV, which can be reacted with hydrazine monohydrate to give a compound of Formula V.
  • the reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IV can be carried out in an organic solvent, for example, dichloroethane, dichloromethane, chloroform or carbon tetrachloride in the presence of a base, for example, pyridine, N-methylmorpholine, triethylamine or diisopropylethylamine.
  • a base for example, pyridine, N-methylmorpholine, triethylamine or diisopropylethylamine.
  • the reaction of a compound of Formula TV with hydrazine monohydrate to give a compound of Formula V can be carried out in an organic solvent, for example, dioxane, ethanol, tetrahydrofuran, diethylether or dimethylformamide.
  • hydrazine sulphate or hydrazine in place of hydrazine monohydrate.
  • Particular illustrative compounds which may be prepared by following Scheme I, for example, include: Phenyl (4-fluorophenyl)carbamate N-(4-Fluorophenyl)hydrazinecarboxamide
  • the compounds of Formulae VIII and X can be prepared by following, for example, the reaction sequence as depicted in Scheme II.
  • a compound of Formula VI (wherein G 1 is the same as defined earlier) can be reacted with a compound of Formula VII to give a compound of Formula VIII, which can undergo N-activation to give a compound of Formula IX (in-sit ⁇ ) (wherein P 1 represents N-activating groups selected form acetyl, propionyl or trifluoro acetyl), which can undergo hydrogenation to give a salt of Formula X (wherein P 2 is acetic acid, propionic acid or trifluoroacetic acid).
  • reaction of a compound of Formula VI with a compound of Formula VII to give compound of Formula VIII can be carried out in presence of a base, for example, sodium carbonate, lithium carbonate or potassium carbonate in water and in an organic solvent, for example, ethanol, methanol, propanol or isopropylalcohol.
  • a base for example, sodium carbonate, lithium carbonate or potassium carbonate in water
  • an organic solvent for example, ethanol, methanol, propanol or isopropylalcohol.
  • IX in-situ
  • N-activating agents for example, acetic acid, propionic acid or trifluoroacetic acid in the presence of a corresponding anhydride, for example, acetic anhydride, propionic anhydride or trifluoroacetic anhydride.
  • X can be carried out under hydrogenating conditions, for example, palladium on carbon or, for example, under catalytic transfer hydrogenation conditions such as ammonium formate and palladium on carbon.
  • the compound of Formula XIII can be prepared by following, for example, the reaction sequence as depicted in Scheme III.
  • a compound of Formula V (wherein G 1 is the same as defined earlier) can be reacted with compound of Formula X to give compound of Formula XI, which can be reacted with a compound of Formula XII (wherein F 1 is alkyl, cycloalkyl or aryl and hal is Cl, Br or I) to give compound of Formula XIII.
  • reaction of a compound of Formula V with compound of Formula X to give a compound of Formula XI can be carried out in an organic solvent, for example, dimethylformamide, dimethylsulphoxide, tetrahydrofuran, diethyl ether or dioxane in the presence of protonating agent, for example, acetic acid.
  • organic solvent for example, dimethylformamide, dimethylsulphoxide, tetrahydrofuran, diethyl ether or dioxane
  • reaction of compound of Formula XI with compound of Formula XII to give a compound of Formula XIII can be carried out in an organic solvent, for example, dioxane, tetrahydrofuran, diethyl ether or dimethylformamide in the presence of a base, for example, potassium carbonate, potassium phosphate, cesium carbonate, lithium carbonate or sodium carbonate and catalyst, for example, copper iodide or palladium (0) or palladium (II) in combination with triphenylphosphine.
  • organic solvent for example, dioxane, tetrahydrofuran, diethyl ether or dimethylformamide
  • a base for example, potassium carbonate, potassium phosphate, cesium carbonate, lithium carbonate or sodium carbonate
  • catalyst for example, copper iodide or palladium (0) or palladium (II) in combination with triphenylphosphine.
  • reaction of compound of Formula XI with compound of Formula XII to give a compound of Formula XIII can be carried out in an organic solvent, for example, dimethylformamide, dioxane, tetrahydrofuran or diethyl ether in the presence of a base, for example, potassium carbonate, cesium carbonate, lithium carbonate or sodium carbonate.
  • organic solvent for example, dimethylformamide, dioxane, tetrahydrofuran or diethyl ether
  • a base for example, potassium carbonate, cesium carbonate, lithium carbonate or sodium carbonate.
  • Step b iV-(4-fluorophenyl)hydrazinecarboxamide
  • the compounds 4-pyridyl carbonitrile (commercially available) (25g, 240.13mmoles), hydroxylamine hydrochloride (61.24g, 881.28mmoles) and sodium carbonate (43.77g, 413.02mmoles) were dissolved in a solution of water (125ml) and ethanol (375ml). The reaction mixture was then stirred for 10 minutes at room temperature followed by refluxing for 17 hrs. The resulting reaction mixture was cooled to room temperature and diluted with ice-cold water. The precipitate thus obtained were collected by filtration, washed with water and dried under vacuum to furnish the title compound.
  • Mass spectrum (m/z, +ve ion mode): 369[M + +l+2] and 367[M + +1].
  • IR spectrum (KBr): 3448, 1706, 1601, 1495 and 1376 cm “1 .
  • Example 5 Synthesis of 2-(cvclohexylmemyl)-4-(4-fluorophenyl)-5-pyridin-4-yl-2,4- dihydro-3H-l,2,4-triazol-3-one (Compound No.12 ⁇
  • potassium carbonate 0.13Og, 0.938 mmol
  • cyclohexylmethyl bromide 0.11 Ig, 0.625mmol
  • Example 6 p38 Inhibition Assay p38 MAP Kinase inhibitory potential was evaluated utilizing the proprietary IQ technology (Pierce Biotechnology). The assay incorporates an iron-containing compound that binds specifically to phosphate groups present on fluorescent dye-labeled phosphorylated peptides which in this case was the Epidermal Growth Factor Receptor Peptide (KRELVEPLTPSGEAPNQALLR). Recombinant activated GST- p38MAP kinase- ⁇ was used at a concentration of 4OnM. The reaction was initiated with lOO ⁇ M ATP.
  • KRELVEPLTPSGEAPNQALLR Epidermal Growth Factor Receptor Peptide
  • the iron-containing compound When bound to the phosphate group, the iron-containing compound was brought into proximity to the flurophore and act as a dark quencher of the fluorescent dye. Results were quantitated by comparing the observed relative fluorescence units of test samples to blanks containing no enzyme. A dose response curve was generated with different concentrations of inhibitor and the IC 50 was calculated using Graph Pad Prism. Compound Nos. 1-25 were tested and showed p38 inhibitory activity in the range of from about 800 ⁇ M to about lOO ⁇ M, for example, from about 800 ⁇ M to about 20 ⁇ M, or from about 80OjLtM to about lO ⁇ M, or from about 800 ⁇ M to about 4 ⁇ M..

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Abstract

La présente invention concerne de nouveaux dérivés de triazolone utilisés comme agents anti-inflammatoires. Les composés de cette invention peuvent être utilisés pour inhiber et prévenir l'inflammation et des pathologies associées, y compris des maladies inflammatoires et auto-immunes telles que la sepsie, l'arthrite rhumatoïde, la maladie intestinale inflammatoire, le diabète de type 1, l'asthme, la maladie pulmonaire obstructive chronique, le rejet de greffe d'organe et le psoriasis. Cette invention concerne également des compositions pharmacologiques contenant les composés de cette invention, ainsi que des méthodes permettant de traiter la sepsie, l'arthrite rhumatoïde, la maladie intestinale inflammatoire, le diabète de type 1, l'asthme, la maladie pulmonaire obstructive chronique, le rejet de greffe d'organe et le psoriasis, ainsi que d'autres troubles inflammatoires et/ou auto-immuns à l'aide de ces composés.
PCT/IB2006/001143 2005-05-03 2006-05-03 Derives de triazolone utilises comme agents anti-inflammatoires Ceased WO2006117657A1 (fr)

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007134862A1 (fr) 2006-05-23 2007-11-29 Bayer Healthcare Ag Imidazolones et triazolones d'aryle substitués comme inhibiteurs des récepteurs de vasopressine
EP1958947A1 (fr) 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibiteurs de la phosphodiestérase de type 4
DE102009013642A1 (de) 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft Substituierte Phenylalaninderivate und deren Verwendung
WO2010105770A1 (fr) 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft 2-acétamido-5-aryl-1,2,4-triazolones substitués et leur utilisation
WO2011023703A1 (fr) 2009-08-27 2011-03-03 Bayer Schering Pharma Aktiengesellschaft 2-acetamido-5-aryl-1,2,4-triazolones hétérocycliquement substituées et leur utilisation
WO2011104322A1 (fr) 2010-02-27 2011-09-01 Bayer Pharma Aktiengesellschaft Aryltriazolone liée à un bis-aryle et son utilisation
WO2012028644A1 (fr) 2010-09-02 2012-03-08 Bayer Pharma Aktiengesellschaft N-phénéthyl-triazolonacétamidessubstitués et leur utilisation
DE102010040924A1 (de) 2010-09-16 2012-03-22 Bayer Schering Pharma Aktiengesellschaft Substituierte Phenylacet- und Phenylpropanamide und ihre Verwendung
US8420666B2 (en) 2007-03-14 2013-04-16 Ranbaxy Laboratories Limited Pyrazolo (3, 4-B) pyridine derivatives as phosphodiesterase inhibitors
WO2013186692A1 (fr) * 2012-06-15 2013-12-19 Glenmark Pharmaceuticals S.A. Composés triazolone utilisés comme inhibiteurs de la mpges-1
US8859601B2 (en) 2008-12-06 2014-10-14 Bayer Intellectual Property Gmbh Substituted benzyl and phenylsulfonyl triazolones, and use thereof
WO2014202505A1 (fr) 2013-06-20 2014-12-24 Bayer Cropscience Ag Dérivés d'arylsulfure et d'arylsulfoxyde utilisés comme acaricides et insecticides
WO2014202510A1 (fr) 2013-06-20 2014-12-24 Bayer Cropscience Ag Dérivés d'arylsulfure et d'arylsulfoxyde utilisés comme acaricides et insecticides
WO2015004028A1 (fr) 2013-07-08 2015-01-15 Bayer Cropscience Ag Dérivés de sulfures et sulfoxydes d'aryles hexacycliques à liaison c‑n utilisés comme pesticides
US9771352B2 (en) 2014-11-03 2017-09-26 Bayer Pharma Aktiengesellschaft Hydroxyalkyl-substituted phenyltriazole derivatives and uses thereof
US9988367B2 (en) 2016-05-03 2018-06-05 Bayer Pharma Aktiengesellschaft Amide-substituted pyridinyltriazole derivatives and uses thereof

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EP1958947A1 (fr) 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibiteurs de la phosphodiestérase de type 4
US8420666B2 (en) 2007-03-14 2013-04-16 Ranbaxy Laboratories Limited Pyrazolo (3, 4-B) pyridine derivatives as phosphodiesterase inhibitors
US8859601B2 (en) 2008-12-06 2014-10-14 Bayer Intellectual Property Gmbh Substituted benzyl and phenylsulfonyl triazolones, and use thereof
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WO2010105750A1 (fr) 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft Dérivés de triazole en tant qu'inhibiteurs des récepteurs de vasopressine pour le traitement de l'insuffisance cardiaque
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WO2011104322A1 (fr) 2010-02-27 2011-09-01 Bayer Pharma Aktiengesellschaft Aryltriazolone liée à un bis-aryle et son utilisation
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WO2012028644A1 (fr) 2010-09-02 2012-03-08 Bayer Pharma Aktiengesellschaft N-phénéthyl-triazolonacétamidessubstitués et leur utilisation
DE102010040187A1 (de) 2010-09-02 2012-03-08 Bayer Schering Pharma Aktiengesellschaft Substituierte N-Phenethyl-triazolonacetamide und ihre Verwendung
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US9949955B2 (en) 2012-06-15 2018-04-24 Glenmark Pharmaceuticals S.A. Triazolone compounds as mPGES-1 inhibitors
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JP2015523353A (ja) * 2012-06-15 2015-08-13 グレンマーク・ファーマシューティカルズ・エスエー ｍＰＧＥＳ−１阻害剤としてのトリアゾロン化合物
US10821100B2 (en) 2012-06-15 2020-11-03 Ichnos Sciences SA Triazolone compounds as mPGES-1 inhibitors
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