WO2006040645A1 - Derives de benzamide n-(3,5-dichloropyridine-4-yle)-2,4,5-alcoxy et 2,3,4 alcoxy en tant qu'inhibiteurs de pde-iv (phosphodiesterase de type iv) pour traiter des maladies inflammatoires telles que l'asthme - Google Patents

Derives de benzamide n-(3,5-dichloropyridine-4-yle)-2,4,5-alcoxy et 2,3,4 alcoxy en tant qu'inhibiteurs de pde-iv (phosphodiesterase de type iv) pour traiter des maladies inflammatoires telles que l'asthme Download PDF

Info

Publication number
WO2006040645A1
WO2006040645A1 PCT/IB2005/003017 IB2005003017W WO2006040645A1 WO 2006040645 A1 WO2006040645 A1 WO 2006040645A1 IB 2005003017 W IB2005003017 W IB 2005003017W WO 2006040645 A1 WO2006040645 A1 WO 2006040645A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
alkyl
heteroaryl
give
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.)
Ceased
Application number
PCT/IB2005/003017
Other languages
English (en)
Inventor
Ramnik Sharma
Kumar Hari Bhushan
Bhargav Pandya
Ram Chander Aryan
Yatendra Kumar
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.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
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
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2006040645A1 publication Critical patent/WO2006040645A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • the present invention relates to benzamide derivatives, which can be used as selective inhibitors of phosphodiesterase (PDE) type IV.
  • PDE phosphodiesterase
  • Compounds disclosed herein can be useful in the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans.
  • COPD chronic obstructive pulmonary disease
  • psoriasis psoriasis
  • allergic rhinitis shock
  • atopic dermatitis Crohn's disease
  • ARDS adult respiratory distress syndrome
  • eosinophilic granuloma allergic conjunctivitis
  • osteoarthritis ulcerative co
  • cyclic adenosine-3 ',5 '-monophosphate exhibits an important role of acting as an intracellular secondary messenger (Sutherland, et al., Pharmacol. Rev., 1960,12, 265). Its intracellular hydrolysis to adenosine 5'- monophosphate (AMP) causes a number of inflammatory conditions which include, but are not limited to, psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis.
  • ARDS adult respiratory distress syndrome
  • PDE cyclic nucleotide phosphodiesterases
  • PDE cyclic nucleotide phosphodiesterase
  • 02/062750 disclose cannabinoid receptor ligands which exhibit anti-inflammatory and immunodulatory activity.
  • WO 00/42020 discloses phenylphenanthridines with PDE-IV inhibiting activity.
  • the present invention provides benzamide derivatives, which can be used for the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases, and the processes for the synthesis of these compounds.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • psoriasis psoriasis
  • allergic rhinitis shock
  • atopic dermatitis Crohn's disease
  • ARDS adult respiratory distress syndrome
  • eosinophilic granuloma allergic conjunctivitis
  • osteoarthritis ulcerative colitis and other inflammatory diseases
  • compositions containing the compounds can be used for the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases.
  • COPD chronic obstructive pulmonary disease
  • Ri is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl;
  • R 2 is aryl, heteroaryl, heterocyclyl or cycloalkyl
  • R 3 is independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or cycloalkylalkyl.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms.
  • 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.
  • R f and R q are independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl ⁇ , nitro, or -SO 2 R 6 (wherein R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl).
  • 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. 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.
  • 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 olefinic 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, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like.
  • Cycloalkylalkyl refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier.
  • alkoxy denotes the group O-alkyl, wherein alkyl is the same as defined above.
  • haloalkyl refers to alkyl (wherein alkyl is the same as defined above) substituted with one or more halogen (F, Cl, Br or I).
  • 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 and the like.
  • 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, benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, and the like.
  • Heterocyclyl can optionally include rings having one or more double bonds. 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, tetrahydro furanyl, dihydro furanyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl or piperazinyl.
  • Heteroarylalkyl refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are as defined earlier.
  • halogen e.g., F, Cl, Br, I
  • Heterocyclyl can optionally include rings having one or more double bonds. 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, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl or piperazinyl
  • Heterocyclylalkyl refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are as defined earlier.
  • 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.
  • phosphodiesterase Type IV enzyme for treatment or prophylaxis of an animal or a human suffering from an inflammatory disease or disorder wherein the disease or disorder is mediated through phosphodiesterase Type IV enzyme.
  • the method includes administration of at least one compound having the structure of Formula I.
  • a method for treatment or prophylaxis of an animal or a human suffering from a disease or disorder associated with phosphodiesterase Type IV enzyme comprising administering to a patient in need thereof, an effective amount of a phosphodiesterase Type IV inhibitor compound as described above.
  • a method for treatment or prophylaxis of an animal or a human suffering from AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases including administration of at least one compound having the structure of Formula I.
  • the compounds of the present invention may be prepared by techniques known in the art.
  • the compounds of the present invention may be prepared following a reaction sequence, for example, as depicted below.
  • Formula XII The compound of Formula XII can be prepared by following the procedure as depicted in Scheme I.
  • a compound of Formula II (wherein R p is alkyl, alkenyl or alkynyl) can be deprotected to give a compound of Formula III, which can undergo O- protection with a compound of Formula P-hal (wherein P is aralkyl (for example benzyl) or alkyl (for example methyl, isopropyl or t-butyl)] to give a compound of Formula IV, which can be reacted with a compound of Formula R k -hal (wherein R k is alkyl substituted with cycloalkyl, aryl, heterocyclyl or heteroaryl) to give a compound of Formula V, which can be deprotected to give a compound of Formula VI, which can be reacted with a compound of Formula VII (wherein X is -H or -COOCH 3 ) to give a compound of Formula VIII
  • boron and aluminum halides for example boron trichloride, aluminum tribromide or aluminum trichloride can also be used in an organic solvent, for example, pentane, benzene, toluene or dichloromethane.
  • the compound of Formula III can undergo O-protection with a compound of Formula P-hal to give a compound of Formula IV in dipolar aprotic solvent, for example, dimethylsulphoxide, dimethylformamide or hexamethylphosphoric triamide in the presence of a base, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide.
  • dipolar aprotic solvent for example, dimethylsulphoxide, dimethylformamide or hexamethylphosphoric triamide
  • a base for example, potassium hydroxide, sodium hydroxide or lithium hydroxide.
  • monomethylation of the para-hydroxyl group can be carried out by using controlled quantity of diazomethane in an organic solvent, for example, diethyl ether, ethanol, isopropanol, methanol or dichloromethane.
  • organic solvent for example, diethyl ether, ethanol, isopropanol, methanol or dichloromethane.
  • the compound of Formula IV can be reacted with a compound of Formula R k -hal to give a compound of Formula V in an organic solvent, for example, dimethylsulphoxide, dimethylformamide, diethyl ether, tetrahydrofuran or dioxane, in the presence of a base, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide.
  • an organic solvent for example, dimethylsulphoxide, dimethylformamide, diethyl ether, tetrahydrofuran or dioxane
  • a base for example, potassium hydroxide, sodium hydroxide or lithium hydroxide.
  • the compound of Formula V (when P is benzyl) can undergo deprotection to give a compound VI, in the presence of deprotecting agent, for example, palladium on carbon in the presence of hydrogen gas or palladium on carbon in ammonium formate solution, in an organic solvent, for example, ethyl acetate or by utilizing hydrochloric acid in acetic acid.
  • deprotecting agent for example, palladium on carbon in the presence of hydrogen gas or palladium on carbon in ammonium formate solution
  • organic solvent for example, ethyl acetate or by utilizing hydrochloric acid in acetic acid.
  • the compound of Formula V (when P is alkyl) can be deprotected to give a compound of Formula VI by following the procedure as described 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.
  • the compound of Formula VI can be reacted with a compound of Formula VII
  • a compound of Formula VIII in an organic solvent, for example, dimethylsulphoxide, dioxane, dimethylformamide, toluene, tetrahydrofuran or diethyl ether, in the presence of a base, for example, potassium hydroxide, sodium hydroxide, butyl lithium, triethyl amine or pyridine with catalyst, for example, benzyltriethyl ammonium chloride, benzyltrimethyl ammonium chloride, benzyltributyl ammonium chloride, tetrabutyl ammonium bromide.
  • organic solvent for example, dimethylsulphoxide, dioxane, dimethylformamide, toluene, tetrahydrofuran or diethyl ether
  • a base for example, potassium hydroxide, sodium hydroxide, butyl lithium, triethyl amine or pyridine with catalyst, for example, benzyltriethyl ammonium chloride,
  • the compound of Formula VIII can be oxidized to give a compound of Formula IX with an oxidizing agent, for example, sodium chlorite, sodium dichromate, potassium permanganate or potassium dichromate, in an organic solvent, for example, acetic acid or formic acid.
  • an oxidizing agent for example, sodium chlorite, sodium dichromate, potassium permanganate or potassium dichromate
  • organic solvent for example, acetic acid or formic acid.
  • the compound of Formula IX can be converted to a compound of Formula X with an acid activating agent, for example, thionyl chloride, phosphorous pentachloride or phosphorous trichloride, in an organic solvent, for example, toluene, benzene or xylene.
  • an acid activating agent for example, thionyl chloride, phosphorous pentachloride or phosphorous trichloride
  • organic solvent for example, toluene, benzene or xylene.
  • the compound of Formula X can be reacted with a compound of Formula XI to give a compound of Formula XII in an organic solvent, for example, tetrahydrofuran, dimethylformamide, diethyl ether or dioxane, in the presence of a base, for example, sodium hydride, diisopropylethylamine or butyl lithium.
  • organic solvent for example, tetrahydrofuran, dimethylformamide, diethyl ether or dioxane
  • a base for example, sodium hydride, diisopropylethylamine or butyl lithium.
  • the compound of Formula XIX can be prepared, for example, by following the reaction procedure as depicted in Scheme II.
  • a compound of Formula XIII can undergo formylation to give a compound of Formula XIV, which can be reacted with a compound of Formula VII (wherein X is -H or -COOCH 3 ) to give a compound of Formula XV, which can be reacted with a compound of Formula R k -hal to give a compound of Formula XVI, which can undergo oxidation to give a compound of Formula XVII, which can be converted to a compound of Formula XVIII (wherein hal is Br, Cl or I), which can be reacted with a compound of Formula XI to give a compound of Formula XIX.
  • the compound of Formula XIII can undergo formylation to give a compound of Formula XIV with a formylation agent, for example, dimethyl formamide, triformamide, tris(diformylamino)methane, tris(dichloromethyl)amine or N,N,N,N-tetraformylhydrazine in the presence of a Lewis acid, for example phosphorous oxychloride, aluminum trichloride or boron trichloride, followed by deprotection with a strong mineral acid, for example, hydrochloric acid, nitric acid or sulphuric acid.
  • a formylation agent for example, dimethyl formamide, triformamide, tris(diformylamino)methane, tris(dichloromethyl)amine or N,N,N,N-tetraformylhydrazine in the presence of a Lewis acid, for example phosphorous oxychloride, aluminum trichloride or boron trich
  • the compound of Formula XIV can be reacted with a compound of Formula VII (wherein X is -COOCH 3 ) to give a compound of Formula XV in an organic solvent, for example dimethylsulphoxide, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane, in the presence of a base, for example, cesium carbonate, sodium carbonate, lithium carbonate or potassium carbonate.
  • an organic solvent for example dimethylsulphoxide, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane
  • a base for example, cesium carbonate, sodium carbonate, lithium carbonate or potassium carbonate.
  • the compound of Formula XIV can be reacted with a compound of Formula VII (when X is -H) to give a compound of Formula XV in an organic solvent, for example, dioxane, dimethylformamide, toluene, dimethylsulphoxide, tetrahydrofuran or diethyl ether, in the presence of a base, for example, sodium hydroxide, butyl lithium, triethyl amine or pyridine with catalyst for example, benzyltriethyl ammonium chloride, benzyltrimethyl ammonium chloride, benzyltributyl ammonium chloride, tetrabutyl ammonium bromide.
  • an organic solvent for example, dioxane, dimethylformamide, toluene, dimethylsulphoxide, tetrahydrofuran or diethyl ether
  • a base for example, sodium hydroxide, butyl lithium, triethyl amine or pyridine
  • the compound of Formula XV can be reacted with a compound of Formula R k -hal to give a compound of Formula XVI in an organic solvent, for example, dimethylsulphoxide, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane, in the presence of a base, for example, potassium hydroxide, sodium hydroxide or lithium hydroxide.
  • a base for example, potassium hydroxide, sodium hydroxide or lithium hydroxide.
  • the compound of Formula XVI can be oxidized to give a compound of Formula
  • XVII with oxidizing agent for example, sodium chlorite, sodium dichromate, potassium permanganate or potassium dichromate, in an organic solvent, for example, acetic acid, or formic acid.
  • oxidizing agent for example, sodium chlorite, sodium dichromate, potassium permanganate or potassium dichromate
  • organic solvent for example, acetic acid, or formic acid.
  • the compound of Formula XVII can be converted to a compound of Formula XVIII with an acid activating group, for example, thionyl chloride, phosphorous pentachloride or phosphorous trichloride, in an organic solvent, for example, toluene, xylene or benzene.
  • an acid activating group for example, thionyl chloride, phosphorous pentachloride or phosphorous trichloride
  • organic solvent for example, toluene, xylene or benzene.
  • the compound of Formula XVIII can be reacted with a compound of Formula XI to give a compound of Formula XIX in an organic solvent, for example, tetrahydrofuran, dimethylformamide, diethyl ether or dioxane, in the presence of a base, for example, sodium hydride, diisopropylethylamine or butyl lithium.
  • organic solvent for example, tetrahydrofuran, dimethylformamide, diethyl ether or dioxane
  • a base for example, sodium hydride, diisopropylethylamine or butyl lithium.
  • the compounds of Formula XXI can be prepared, for example, following the procedure as depicted in Scheme III.
  • the compound of Formula XX can undergo N- oxidation to give a compound of Formula XXI.
  • the compound of Formula XX can be reacted with an oxidizing agent, for example, magnesium monoperoxyphthalate hexahydrate (MMPP), metachloroperbenzoic acid (m-CPBA), hydrogen peroxide (H 2 O 2 ) or oxone (KHSO 5 ) in the presence of a solvent mixture, for example, dichloromethane in methanol to give a compound of Formula XXI.
  • an oxidizing agent for example, magnesium monoperoxyphthalate hexahydrate (MMPP), metachloroperbenzoic acid (m-CPBA), hydrogen peroxide (H 2 O 2 ) or oxone (KHSO 5 ) in the presence of a solvent mixture, for example, dichloromethane in methanol to give a compound of
  • ethers are specified at a position ortho to the amide group
  • one skilled in the art could optionally deprotect them to their respective alcohols, for example deprotection of alkyl ethers (such as methyl or ethyl ethers) to their corresponding alcohols can be carried out with hydrochloric acid or hydrobromic acid in aqueous acetic acid or following the procedure a described 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.,
  • Suitable salts of the compounds represented by the Formula I can also be prepared so as to solubilize the compound in aqueous medium for biological evaluations, as well as to be compatible with various dosage formulations and also to aid in the bioavailability of the compounds.
  • examples of such salts include pharmacologically acceptable salts such as inorganic acid salts (for example, hydrochloride, hydrobromide, sulphate, nitrate and phosphate), organic acid salts (for example, acetate, tartarate, citrate, fumarate, maleate, tolounesulphonate and methanesulphonate).
  • These salts may be prepared by various techniques, such as treating the compound with an equivalent amount of inorganic or organic, acid or base in a suitable solvent.
  • the compounds described herein may be administered to an animal for treatment orally, or by a parenteral route.
  • the pharmaceutical compositions described herein can be produced and administered in dosage units, each unit containing a certain amount of at least one compound described herein and/or at least one physiologically acceptable addition salt thereof.
  • the dosage may be varied over extremely wide limits, as the compounds are effective at low dosage levels and relatively free of toxicity.
  • the compounds may be administered in the low micromolar concentration, which is therapeutically effective, and the dosage may be increased as desired up to the maximum dosage tolerated by the patient.
  • the compounds described herein can be produced and formulated as their enantiomers, diastereomers, N-Oxides, polymorphs, solvates and pharmaceutically acceptable salts, as well as metabolites having the same type of activity.
  • Pharmaceutical compositions comprising the molecules of Formula I or metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with pharmaceutically acceptable carrier and optionally included excipient can also be produced.
  • Step b 4-(Benzyloxy)-5-hydroxy-2-methoxy benzaldehyde
  • Step c 4-Benzyloxy-5-(cyclopropyImethoxy)-2-methoxy benzaldehyde
  • Step e 5-(Cyclopropylmethoxy)-4-(difluoromethoxy)-2-methoxy benzaldehyde
  • Step f 5-(Cyclopropylmethoxy)-4-difluoromethoxy-2-methoxy benzoic acid
  • Step g 5-Cyclopropylmethoxy-N-(3,5-dichloropyridin-4-yl)-4-difluoromethoxy-2- methoxy benzamide (Compound No. 1)
  • the acid chloride thus obtained was dissolved in tetrahydrofuran (5 ml) and this mixture was added dropwise to an already 15 minutes stirred mixture of 3,5- dichloro-4-amino pyridine (0.7 g, 0.0043 mol) and sodium hydride (60%, 0.38 g, 0.0095 mol) in tetrahydrofuran (5 ml) at 15 0 C.
  • the reaction mixture was stirred for approximately 2 hours and subsequently poured the reaction mass into water (50 ml) with constant stirring. It was acidified with hydrochloric acid (3 ml) and extracted the product with ethyl acetate, washed with water, dried over anhydrous sodium sulphate and evaporated the solvent under reduced pressure.
  • Step c 4-(Difluoromethoxy)-3-hydroxy-2-methoxy benzaldehyde
  • Step d 3-(Cyclopropylmethoxy)-4-(difluoromethoxy)-2-methoxy benzaldehyde
  • Step e 3-(Cyclopropylmethoxy)-4-(difluoromethoxy)-2-methoxy benzoic acid
  • sodium chlorite solution (0.16 g, 0.0017 mol in 0.5 ml OfH 2 O) maintaining the temperature below 15°C.
  • the resulting reaction mixture was stirred at 8°C for 1 hour and then at room temperature for 1 hour followed by the addition of water.
  • the product was extracted with ethyl acetate.
  • the organic layer was washed with water and dried over anhydrous sodium sulphate.
  • the compound No. 1 (0.2 g, 0.00046 mol) was dissolved in a mixture of dichloromethane (1 ml) and methanol (1 ml) followed by the addition of magnesium monoperoxy- phthalate hexahydrate (MMPP) (0.457 g) and stirred for 24 hours at 40°C. To the resulting reaction mixture was added dichloromethane (1 ml), methanol (1 ml) and magnesium monoperoxyphthalate hexahydrate (0.248 g) and stirred for 12 hours. This process was repeated one more time.
  • MMPP magnesium monoperoxy- phthalate hexahydrate
  • PDE-IV Enzyme Assay The efficacy of compounds as PDE-4 inhibitor was determined by an enzyme assay (Burnouf et al.; J. Med. Chem., 2000, 43:4850-4867).
  • the PDE-4 enzyme source used was U937 cell cytosolic fraction prepared by sonication. The enzyme reaction was carried out, with the cytosolic fraction as the enzyme source, in the presence of cAMP (1 ⁇ M) at 30 0 C in the presence or absence of NCE for 45 -60 min. An aliquot of this reaction mixture was taken further for the ELISA assay to determine level of cAMP in the sample. The concentration of the cAMP in the sample directly correlates with the degree of PDE-4 enzyme inhibition.
  • Results were expressed as percent control and the IC 50 values of test compounds 1 and 2 (three test repetitions each) were found to be approximately 1.9 ( ⁇ 0.7) and 2.3 ( ⁇ 0.9) nM, respectively.
  • the values for rolipram (7 repetitions) and rofiumilast (two repetitions) were 463 ( ⁇ 103 and 0.051 ( ⁇ 0.028) nM, respectively.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés de benzamide pouvant servir d'inhibiteurs sélectifs de la phosphodiestérase (PDE) de type IV de formule (I), de ses sels pharmaceutiquement acceptables, de ses solvates pharmaceutiquement acceptables, ses énantiomères, diastéréomères ou oxydes N. Dans la formule, R1 représente hydrogène, alkyle, alcényle, alkynyle, aryle, cycloalkyle, hétéroaryle, hétérocyclyle, aralkyle, hétérocyclylalkyle, hétéroarylalkyle ou cycloalkylalkyle; R2 signifie aryle, hétéroaryle, hétérocyclyle ou cycloalkyle; et R3 désigne alkyle, alcényle, alkynyle, aryle, cycloalkyle, hétéroaryle, hétérocyclyle, aralkyle, hétérocyclylalkyle, hétéroarylalkyle ou cycloalkylalkyle. Les composés de l'invention peuvent s'avérer utiles dans le traitement de maladies inflammatoires, le SIDA, l'asthme, l'arthrite, la bronchite, la bronchopneumopathie chronique obstructive (BPCO), le psoriasis, la rhinite allergique, l'état de choc, la dermatite atopique, la maladie de Crohn, le syndrôme de détresse respiratoire de l'adulte, le granulome éosinophile des os, la conjonctivite allergique, l'ostéoarthrite et la rectocolite hémorragique.
PCT/IB2005/003017 2004-10-11 2005-10-11 Derives de benzamide n-(3,5-dichloropyridine-4-yle)-2,4,5-alcoxy et 2,3,4 alcoxy en tant qu'inhibiteurs de pde-iv (phosphodiesterase de type iv) pour traiter des maladies inflammatoires telles que l'asthme Ceased WO2006040645A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1960/DEL/2004 2004-10-11
IN1960DE2004 2004-10-11

Publications (1)

Publication Number Publication Date
WO2006040645A1 true WO2006040645A1 (fr) 2006-04-20

Family

ID=35747438

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/003017 Ceased WO2006040645A1 (fr) 2004-10-11 2005-10-11 Derives de benzamide n-(3,5-dichloropyridine-4-yle)-2,4,5-alcoxy et 2,3,4 alcoxy en tant qu'inhibiteurs de pde-iv (phosphodiesterase de type iv) pour traiter des maladies inflammatoires telles que l'asthme

Country Status (1)

Country Link
WO (1) WO2006040645A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010513334A (ja) * 2006-12-22 2010-04-30 レオ ファーマ アクティーゼルスカブ Ｐｄｅ４阻害剤として有用な置換アセトフェノン
WO2010142752A1 (fr) * 2009-06-11 2010-12-16 F. Hoffmann-La Roche Ag Composés inhibiteurs des kinases janus et procédés
CN102276522A (zh) * 2011-06-15 2011-12-14 无锡泓兴生物医药科技有限公司 一种制备罗氟司特的方法及其中间体

Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3415841A (en) * 1965-06-12 1968-12-10 Kuhlmann Ets 6-amino-chloro-indazoles and n-acylated derivatives thereof
JPS5522634A (en) * 1978-08-03 1980-02-18 Hisamitsu Pharmaceut Co Inc Novel aminonicotinic acid derivative
JPS5869812A (ja) * 1981-10-22 1983-04-26 Chugai Pharmaceut Co Ltd 血糖降下剤
US4720500A (en) * 1985-07-11 1988-01-19 Rhone-Poulenc Sante N-1,8-naphthyridin-2-yl amides useful as immunostimulants
EP0602478A1 (fr) * 1992-12-18 1994-06-22 F. Hoffmann-La Roche Ag Procédé pour la production des dérivés de N4-acyl-5'-déoxy-5-fluorocytidine
WO1996011690A1 (fr) * 1994-10-14 1996-04-25 Institut De Recherche Jouveinal Diazepino-indoles inhibiteurs de phosphodiesterases iv
EP0714898A1 (fr) * 1994-06-21 1996-06-05 Otsuka Pharmaceutical Factory, Inc. DERIVE DE PYRAZOLO [1,5-a]PYRIMIDINE
WO1996021435A1 (fr) * 1995-01-10 1996-07-18 Euro-Celtique, S.A. Composes et procede pour inhiber la phosphodiesterase iv
WO1997014681A1 (fr) * 1995-10-16 1997-04-24 Fujisawa Pharmaceutical Co., Ltd. Composes heterocycliques tels que des h+-atpases
JPH10101672A (ja) * 1996-08-06 1998-04-21 Otsuka Pharmaceut Factory Inc アデノシン増強剤
WO1999005104A1 (fr) * 1997-07-23 1999-02-04 Pfizer Pharmaceuticals Inc. Composes d'indole en tant qu'inhibiteurs de cox-2
EP0915093A1 (fr) * 1996-06-06 1999-05-12 Otsuka Pharmaceutical Factory, Inc. Derives d'amides
JPH11222435A (ja) * 1998-02-05 1999-08-17 Otsuka Pharmaceut Factory Inc 一酸化窒素合成酵素阻害剤
WO1999061013A2 (fr) * 1998-05-22 1999-12-02 Avanir Pharmaceuticals COMPOSES AYANT DES PROPRIETES AFFECTANT LES IgE
WO2000042018A1 (fr) * 1999-01-15 2000-07-20 Byk Gulden Lomberg Chemische Fabrik Gmbh 6-phenylphenanthridines polysubstitues a activite inhibant pde-iv
EP1052254A1 (fr) * 1998-01-26 2000-11-15 Eisai Co., Ltd. Derives heterocycliques azotes et medicaments produits a partir de ces derives
WO2001093909A2 (fr) * 2000-06-06 2001-12-13 Glaxo Group Limited Procede de traitement du cancer
WO2002064545A1 (fr) * 2001-02-13 2002-08-22 Aventis Pharma Deutschland Gmbh Amines indanyle acyles et leurs utilisation comme agents pharmaceutiques
WO2002092062A2 (fr) * 2001-05-15 2002-11-21 Leo Pharma A/S Combinaison d'un analogue de vitamine d et d'un analogue de pyrimidine nucleoside
WO2002096879A1 (fr) * 2001-05-31 2002-12-05 Sanofi-Synthelabo Derives d'aminoquinoline et d'aminopyrridine et leur utilisation comme ligands d'adenosine a3
WO2004000806A1 (fr) * 2002-06-24 2003-12-31 Elbion Ag Amides d'acides amines cycliques utilises comme inhibiteurs de la pde 4
DE10229762A1 (de) * 2002-07-03 2004-01-22 Aventis Pharma Deutschland Gmbh Pyrazoloisoquinolinenderivaten zur Inhibierung von NFkappaB-induzierende Kinase
WO2004029055A1 (fr) * 2002-09-30 2004-04-08 Bayer Pharmaceuticals Corporation Derives d'azole-pyrimidines fondues

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3415841A (en) * 1965-06-12 1968-12-10 Kuhlmann Ets 6-amino-chloro-indazoles and n-acylated derivatives thereof
JPS5522634A (en) * 1978-08-03 1980-02-18 Hisamitsu Pharmaceut Co Inc Novel aminonicotinic acid derivative
JPS5869812A (ja) * 1981-10-22 1983-04-26 Chugai Pharmaceut Co Ltd 血糖降下剤
US4720500A (en) * 1985-07-11 1988-01-19 Rhone-Poulenc Sante N-1,8-naphthyridin-2-yl amides useful as immunostimulants
EP0602478A1 (fr) * 1992-12-18 1994-06-22 F. Hoffmann-La Roche Ag Procédé pour la production des dérivés de N4-acyl-5'-déoxy-5-fluorocytidine
EP0714898A1 (fr) * 1994-06-21 1996-06-05 Otsuka Pharmaceutical Factory, Inc. DERIVE DE PYRAZOLO [1,5-a]PYRIMIDINE
WO1996011690A1 (fr) * 1994-10-14 1996-04-25 Institut De Recherche Jouveinal Diazepino-indoles inhibiteurs de phosphodiesterases iv
WO1996021435A1 (fr) * 1995-01-10 1996-07-18 Euro-Celtique, S.A. Composes et procede pour inhiber la phosphodiesterase iv
WO1997014681A1 (fr) * 1995-10-16 1997-04-24 Fujisawa Pharmaceutical Co., Ltd. Composes heterocycliques tels que des h+-atpases
EP0915093A1 (fr) * 1996-06-06 1999-05-12 Otsuka Pharmaceutical Factory, Inc. Derives d'amides
JPH10101672A (ja) * 1996-08-06 1998-04-21 Otsuka Pharmaceut Factory Inc アデノシン増強剤
WO1999005104A1 (fr) * 1997-07-23 1999-02-04 Pfizer Pharmaceuticals Inc. Composes d'indole en tant qu'inhibiteurs de cox-2
EP1052254A1 (fr) * 1998-01-26 2000-11-15 Eisai Co., Ltd. Derives heterocycliques azotes et medicaments produits a partir de ces derives
JPH11222435A (ja) * 1998-02-05 1999-08-17 Otsuka Pharmaceut Factory Inc 一酸化窒素合成酵素阻害剤
WO1999061013A2 (fr) * 1998-05-22 1999-12-02 Avanir Pharmaceuticals COMPOSES AYANT DES PROPRIETES AFFECTANT LES IgE
WO2000042018A1 (fr) * 1999-01-15 2000-07-20 Byk Gulden Lomberg Chemische Fabrik Gmbh 6-phenylphenanthridines polysubstitues a activite inhibant pde-iv
WO2001093909A2 (fr) * 2000-06-06 2001-12-13 Glaxo Group Limited Procede de traitement du cancer
WO2002064545A1 (fr) * 2001-02-13 2002-08-22 Aventis Pharma Deutschland Gmbh Amines indanyle acyles et leurs utilisation comme agents pharmaceutiques
WO2002092062A2 (fr) * 2001-05-15 2002-11-21 Leo Pharma A/S Combinaison d'un analogue de vitamine d et d'un analogue de pyrimidine nucleoside
WO2002096879A1 (fr) * 2001-05-31 2002-12-05 Sanofi-Synthelabo Derives d'aminoquinoline et d'aminopyrridine et leur utilisation comme ligands d'adenosine a3
WO2004000806A1 (fr) * 2002-06-24 2003-12-31 Elbion Ag Amides d'acides amines cycliques utilises comme inhibiteurs de la pde 4
DE10229762A1 (de) * 2002-07-03 2004-01-22 Aventis Pharma Deutschland Gmbh Pyrazoloisoquinolinenderivaten zur Inhibierung von NFkappaB-induzierende Kinase
WO2004029055A1 (fr) * 2002-09-30 2004-04-08 Bayer Pharmaceuticals Corporation Derives d'azole-pyrimidines fondues

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2003, GARNIER, ETHEL ET AL: "New access to oxazolopyridines via hydroxyamidine derivatives; application to quinolines", XP002367914, retrieved from STN Database accession no. 2003:790967 *
DATABASE CHEMCATS 2001, ASINEX EXPRESS GOLD COLLECTION, Database accession no. 2001:543291 CHEMCATS *
DATABASE REGISTRY 5 January 2001 (2001-01-05), XP002367915, Database accession no. RN: 312943-96-7 *
SYNTHESIS , (13), 2033-2040 CODEN: SYNTBF; ISSN: 0039-7881, 2003 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010513334A (ja) * 2006-12-22 2010-04-30 レオ ファーマ アクティーゼルスカブ Ｐｄｅ４阻害剤として有用な置換アセトフェノン
US8148537B2 (en) * 2006-12-22 2012-04-03 Leo Pharma A/S Substituted acetophenones useful as PDE4 inhibitors
US8324394B2 (en) 2006-12-22 2012-12-04 Leo Pharma A/S Substituted acetophenones useful as PDE4 inhibitors
US8497380B2 (en) 2006-12-22 2013-07-30 Leo Pharma A/S Substituted acetophenones useful as PDE4 inhibitors
WO2010142752A1 (fr) * 2009-06-11 2010-12-16 F. Hoffmann-La Roche Ag Composés inhibiteurs des kinases janus et procédés
CN102459187A (zh) * 2009-06-11 2012-05-16 弗·哈夫曼-拉罗切有限公司 Janus激酶抑制化合物和方法
JP2012529470A (ja) * 2009-06-11 2012-11-22 エフ．ホフマン−ラ ロシュ アーゲー ヤーヌスキナーゼ阻害剤化合物および方法
US8486950B2 (en) 2009-06-11 2013-07-16 F. Hoffmann-La Roche Ag Janus kinase inhibitor compounds and methods
CN102459187B (zh) * 2009-06-11 2015-06-17 弗·哈夫曼-拉罗切有限公司 Janus激酶抑制化合物和方法
AU2010258597B2 (en) * 2009-06-11 2016-02-25 F. Hoffmann-La Roche Ag Janus kinase inhibitor compounds and methods
CN102276522A (zh) * 2011-06-15 2011-12-14 无锡泓兴生物医药科技有限公司 一种制备罗氟司特的方法及其中间体
CN102276522B (zh) * 2011-06-15 2013-04-17 无锡泓兴生物医药科技有限公司 一种制备罗氟司特的方法及其中间体

Similar Documents

Publication Publication Date Title
TWI825524B (zh) 用於合成2-羥基-6-((2-(1-異丙基-1h-吡唑-5-基)-吡啶-3-基)甲氧基)苯甲醛之方法
JP6880127B2 (ja) 多環式カルバモイルピリドン化合物の合成
RU2135498C1 (ru) Пиразоло- и пирролопиридины
JP4248605B2 (ja) ピリジン―２―イル―メチルアミン誘導体、それらの製造方法および医薬としてのそれらの適用
JPS63139182A (ja) チアゾリジンジオン誘導体の製造法
SK282338B6 (sk) N-Heteroarylpyridínsulfónamidové deriváty, spôsob prípravy, medziprodukty a použitie týchto derivátov ako antagonistov endotelínu
CN106660996B (zh) 作为pde4抑制剂的2,5-取代的嘧啶类
CA2828337A1 (fr) Derives de fluoro-pyridinone utiles en tant qu'agents antibacteriens
KR890003839B1 (ko) 시클로펜타[d]피리미딘 유도체의 제조방법
EP3310772A1 (fr) Dérivés spiro [cyclobutane -1,3 '-indolin]-2 '-one utilisés en tant qu'inhibiteurs de bromodomaines
JP2021501184A (ja) Ｐ２ｘ３及び／又はｐ２ｘ２／３受容体アンタゴニスト、それを含む医薬組成物及びその使用
HUP0102646A2 (hu) Foszfodiészteráz 4 gátló ftálazinszármazékok és e vegyületeket tartalmazó gyógyászati készítmények
TW202402741A (zh) 用於製備可溶性鳥苷酸環化酶刺激劑之新穎方法及中間物
JP2008530078A (ja) Ｉｖ型ホスホジエステラーゼの阻害剤
WO2007031977A2 (fr) Inhibiteurs de la phosphodiesterase
RS20060206A (sr) Derivati aminopiridina kao inhibitori inducibilne no-sintaze
US12297193B2 (en) PTPN2/PTP1B degrader and therapeutic method thereof
WO2006040645A1 (fr) Derives de benzamide n-(3,5-dichloropyridine-4-yle)-2,4,5-alcoxy et 2,3,4 alcoxy en tant qu'inhibiteurs de pde-iv (phosphodiesterase de type iv) pour traiter des maladies inflammatoires telles que l'asthme
KR900003497B1 (ko) 퀴나졸린디온 및 피리도피리미딘디온 및 이들을 함유하는 제약 조성물
KR950011748B1 (ko) 술펜아미드 유도체 및 그의 제조방법
AU2019424628B2 (en) 1,2,3,4-tetrahydroquinoxaline derivative, preparation method therefor and application thereof
JP2022532875A (ja) Ｃｒａｃチャネル阻害剤の合成
EP1879884B1 (fr) Inhibiteurs de la phosphodiesterase a base d'azole
WO2007004041A2 (fr) Nouveaux composes ainsi qu'utilisation pharmaceutique de ceux-ci
JP2007522181A (ja) シクロオキシゲナーゼ−１及びシクロオキシゲナーゼ−２阻害剤としての置換アゼチジン化合物、ならびにそれらの調製、および薬剤としての使用

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05818852

Country of ref document: EP

Kind code of ref document: A1