[go: up one dir, main page]

WO2006040650A1 - Derives de 4-methoxyacridine-1-carboxamide et les analogues phenazine et oxanthrene utilises comme inhibiteurs pde4 pour le traitement de l'asthme et la maladie pulmonaire chronique (copd) - Google Patents

Derives de 4-methoxyacridine-1-carboxamide et les analogues phenazine et oxanthrene utilises comme inhibiteurs pde4 pour le traitement de l'asthme et la maladie pulmonaire chronique (copd) Download PDF

Info

Publication number
WO2006040650A1
WO2006040650A1 PCT/IB2005/003031 IB2005003031W WO2006040650A1 WO 2006040650 A1 WO2006040650 A1 WO 2006040650A1 IB 2005003031 W IB2005003031 W IB 2005003031W WO 2006040650 A1 WO2006040650 A1 WO 2006040650A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
substituted
unsubstituted
compound
compound according
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/IB2005/003031
Other languages
English (en)
Inventor
Balasubramanian Gopalan
Laxmikant Atmaram Gharat
Neelima Khairatkar-Joshi
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.)
Ichnos Sciences SA
Original Assignee
Glenmark Pharmaceuticals SA
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 Glenmark Pharmaceuticals SA filed Critical Glenmark Pharmaceuticals SA
Publication of WO2006040650A1 publication Critical patent/WO2006040650A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel tricyclic phosphodiesterase type 4 (PDE4) inhibitors and analogs, tautomers, enantiomers, diasteromers, regioisomers, stereoisomers, polymorphs,- pharmaceutically acceptable salts, appropriate N-oxides, and pharmaceutically acceptable solvates thereof, pharmaceutical compositions 5 containing them, and their use for treating conditions mediated by PDE-IV inhibition, such as asthma and chronic obstructive pulmonary disease (COPD).
  • PDE4 tricyclic phosphodiesterase type 4
  • Airway inflammation characterizes a number of severe lung diseases including 0 asthma and chronic obstructive pulmonary disease (COPD).
  • Events leading to airway obstruction include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production.
  • the airways of asthmatic patients are infiltrated by inflammatory leukocytes, of which the eosinophil is the most prominent component. The magnitude 5 of asthmatic reactions is correlated with the number of eosinophils present in the lungs.
  • eosinophils The accumulation of eosinophils is found dramatically in the lungs of asthmatic patients although there are very few in the lungs of a normal individual. They are capable of lysing and activating cells and destroying tissues. When 0 activated, they synthesize and release inflammatory cytokines such as IL-I, IL-3, TNF- ⁇ and inflammatory mediators such as PAF, LTD4 and related oxygen species that can produce edema and broncho-constriction.
  • Tumor necrosis factor (TNF- ⁇ ) was also known to be involved in the pathogenesis of a number of autoimmune and inflammatory diseases. Consequently, manipulation of the cytokine signaling or biosynthetic pathways associated with these proteins may provide therapeutic benefit in those disease states.
  • TNF- ⁇ production in pro- inflammatory cells becomes attenuated by an elevation of intracellular cyclic adenosine 3 ',5 '-monophosphate (cAMP).
  • cAMP cyclic adenosine 3 ',5 '-monophosphate
  • PDE phosphodiesterase family of enzymes.
  • the phosphodiesterase enzymes play an integral role in cell signaling mechanisms by hydrolyzing cAMP and cGP to their inactive 5' forms. Inhibition of PDE enzymes thus results in an elevation of cAMP and/or cGP levels and alters intracellular responses to extra cellular signals by affecting the processes mediated by cyclic nucleotides.
  • PDEs mammalian cyclic nucleotide phosphodiesterases
  • Phosphodiesterase type 4 is an enzyme which regulates activities in cells which lead to inflammation in the lungs.
  • PDE4 a cAMP-specific and Ca +2 - independent enzyme, is a key isozyme in the hydrolysis of cAMP in mast cells, basophils, eosinophils, monocytes and lymphocytes.
  • the association between cAMP elevation in inflammatory cells with airway smooth muscle relaxation and inhibition of mediator release has led to widespread interest in the design of PDE4 inhibitors [Trophy,T.J., Am. J. Respir. Crit. Care Med., 157, 351-370 (1998) which is herein incorporated by reference in its entirety].
  • TNF- ⁇ Excessive or unregulated TNF- ⁇ production has been implicated in mediating or exacerbating a number of undesirable physiological conditions such as diseases including osteoarthritis, and other arthritic conditions, septic shock, endotoxic shock, respiratory distress syndrome and bone resorption diseases. Since TNF- ⁇ also participates in the onset and progress of autoimmune diseases, PDE4 inhibitors may find utility as therapeutic agents for rheumatoid arthritis, multiple sclerosis and Crohn's disease. [Nature Medicine, I, 211- 214 (1995) and ibid., 244-248 which are herein incorporated by reference in their entireties].
  • PDE4 family has grown to include four subtypes - PDE4A to PDE4D, each encoded by a distinct gene ⁇ British Journal of Pharmacology; 1999; v.128; p.l 393-1398), which is herein incorporated by reference in its entirety. It has been demonstrated that increasing cAMP levels within these cells results in suppression of cell activation, which in turn inhibits the production and release of pro-inflammatory cytokines such as TNF- ⁇ . Since eosinophilis are believed to be a critical pro-inflammatory target for asthma, identification of the expression of the PDE-4 gene family in eosinophils led to the PDE-4 as a potential therapeutic target for asthma.
  • PDE-4 inhibitors Unfortunately, is limited due to their undesirable side effect profile which include nausea and emesis (due to action on PDE-4 in the central nervous system) and gastric acid secretion due to action on PDE- 4 in parietal cells in the gut.
  • RolipramTM One of the earliest PDE-4 inhibitors, RolipramTM, was withdrawn from clinical development because of their severe unacceptable side effect profile. Zeller E. et.
  • PDE-4 isozymes may have therapeutic efficacy in the treatment of inflammatory diseases, such as asthma and other respiratory diseases, without the undesirable side effects of prior non-selective PDE-4 inhibitors.
  • the present invention relates to new heterocyclic compounds which inhibit PDE-4 having the formula below:
  • B is O, S or NR a
  • D is O, S or NR a ;
  • R 4 is hydrogen, substituted or unsubstituted alkyl, hydroxyl, -0R a , substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic ring; each dotted line [ — ] in the central ring represents an optional double bond; and analogs, tautomers, regioisomers, stereoisomers, enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, N-oxides, and pharmaceutically acceptable solvates thereof. These compounds may also be included in pharmaceutical compositions.
  • Ar is an optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which the optional substituents (one or more) may be same or different and are independently selected from hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, such as a Ci -6 alkyl, e.g., methyl, ethyl, n-propyl, 1 -methyl ethyl (isopropyl), n-butyl, n-pentyl, and 1,1 -dimethyl ethyl (t-butyl).
  • Ci -6 alkyl e.g., methyl, ethyl, n-propyl, 1 -methyl ethyl (isopropyl), n-butyl, n-pentyl, and 1,1 -dimethyl ethyl (t-butyl).
  • C 1-6 alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, and 2-butenyl.
  • alkynyl refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH 3 and - OC 2 H 5 .
  • alkylcarbonyl denotes an alkyl group as defined above attached via a carbonyl linkage to the rest of the molecule. Representative examples of such groups are -C(O)CH 3 , and -C(O)C 2 H 5 .
  • alkoxycarbonyl denotes an alkoxy group as defined above attached via a carbonyl linkage to the rest of the molecule.
  • Representative examples of such groups are -C(O)-OCH 3 , and -C(O)-OC 2 H 5 .
  • alkylcarbonyloxy denotes an alkylcarbonyl group as defined above attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -0-C(O)CH 3 , and -0-C(O)C 2 H 5 .
  • alkylamino denotes an alkyl group as defined above attached via an amino linkage to the rest of the molecule. Representative examples of such groups are -NH 2 CH 3 , -NH(CH 3 ) 2 , and -N(CH 3 ) 3 .
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 and -C 2 H 5 C 6 H 5 .
  • heterocyclic ring refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidiny
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroarylalkyl refers to a heteroaryl ring radical as defined above directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heterocyclyl refers to a heterocylic ring radical as defined above.
  • the heterocylcyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heterocyclylalkyl refers to a heterocylic ring radical as defined above directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • cyclic ring refers to a cyclic ring containing 3-10 carbon atoms.
  • protecting group includes, but is not limited to, carbobenzyloxy (CBZ) and tert-butyloxy carbonyl (BOC).
  • halogen refers to radicals of fluorine, chlorine, bromine and iodine.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, thiamine, and the like; salts of chiral bases such as alkylphenylamine, glycinol, phenyl glycinol and the like; salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, and the like; quaternary ammonium salts
  • salts include acid addition salts where appropriate, such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.
  • “Delivering" a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by local or by systemic administration of the active ingredient to the host.
  • “A subject” or “a patient” or “a host” refers to a mammalian animal, preferably a human.
  • Treating” or “treatment” of a state, disorder or condition includes:
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • Another aspect of the invention is a method of treating inflammatory diseases, disorders and conditions characterized by or associated with an undesirable inflammatory immune response and diseases and conditions induced by or associated with an excessive secretion of TNF- ⁇ and PDE-4 which comprises administering to a subject a therapeutically effective amount of a compound according to formula 1.
  • Another aspect of the invention is a method of treating inflammatory conditions and immune disorders in a . subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound according to formula 1.
  • Preferred inflammatory conditions and immune disorders include, but are not limited to, asthma, bronchial asthma, chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohns disease, psoraisis, uticaria, adult vernal cojunctivitis, respiratory distress syndrome, rhematoid spondylitis, osteoarthritis, gouty arthritis, uveitis, allergic conjunctivitis, inflammatory bowel conditions, ulcerative coalitis, eczema, atopic dermatitis and chronic inflammation. Further preferred are allergic inflammatory conditions.
  • inflammatory conditions and immune disorders selected from inflammatory conditions or immune disorders of the lungs, joints, eyes, bowels, skin or heart.
  • inflammatory conditions chosen from asthma and chronic obstructive pulmonary disease.
  • Another aspect of the invention is a method for abating inflammation in an affected organ or tissue including delivering to the organ or tissue a therapeutically effective amount of a compound according to Formula 1.
  • Another aspect of the invention is a method of treating diseases of the central nervous system in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound according to Formula 1.
  • Preferred diseases of the central nervous system include, but are not limited to, depression, amnesia, dementia, Alzheimers disease, cardiac failure, shock and cerebrovascular disease.
  • Another aspect of the invention is a method of treating insulin resistant diabetes in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound according to Formula 1.
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
  • the classic symptoms of acute inflammation are redness, elevated temperature, swelling, and pain in the affected area, and loss of function of the affected organ.
  • Symptoms and signs of inflammation associated with specific conditions include: • rheumatoid arthritis- pain, swelling, warmth and tenderness of the involved joints, generalized and morning stiffness; • insulin-dependent diabetes mellitus- insulitis; this condition can lead to a variety of complications with an inflammatory component, including: retinopathy, neuropathy, nephropathy, coronary artery disease, peripheral vascular disease, and cerebrovascular disease; • autoimmune thyroiditis- weakness, constipation, shortness of breath, puffmess of the face, hands and feet, peripheral edema, and bradycardia;
  • inflammatory skin disorders such as , eczema, other dermatites (e.g., atopic, contact), psoriasis, burns induced by UV radiation (sun rays and similar UV sources)- erythema, pain, scaling, swelling, tenderness;
  • inflammatory bowel disease such as Crohn's disease, ulcerative colitis- pain, diarrhea, constipation, rectal bleeding, fever, arthritis;
  • heart tissue injury due to myocardial ischemia- pain, shortness of breath
  • lung injury such as that which occurs in adult respiratory distress syndrome- shortness of breath, hyperventilation, decreased oxygenation, pulmonary infiltrates
  • inflammation accompanying infection such as sepsis, septic shock, toxic shock syndrome- fever, respiratory failure, tachycardia, hypotension, leukocytosis;
  • nephritis e.g., glomerulonephritis
  • oliguria e.g., urinalysis
  • Type II diabetes- end organ complications including cardiovascular, ocular, renal, and peripheral vascular disease ,lung fibrosis- hyperventilation, shortness of breath, decreased oxygenation;
  • vascular disease such as atherosclerosis and restenosis- pain, loss of sensation, diminished pulses, loss of function and alloimmunity leading to transplant rejection- pain, tenderness, fever.
  • Subclinical symptoms include without limitation diagnostic markers for inflammation the appearance of which may precede the manifestation of clinical symptoms.
  • One class of subclinical symptoms is immunological symptoms, such as the invasion or accumulation in an organ or tissue of proinflammatory lymphoid cells or the presence locally or peripherally of activated pro-inflammatory lymphoid cells recognizing a pathogen or an antigen specific to the organ or tissue. Activation of lymphoid cells can be measured by techniques known in the art.
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, per day may be used.
  • a most preferable dosage is about 0.5 mg to about 250 mg per day.
  • the exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the compounds of the present invention are dispensed in unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.05 mg to about 1000 mg, preferably from about 0.5 mg to about 250 mg of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
  • the compounds of formula (I) may be prepared by the following processes.
  • the compounds of formula (1) wherein Y is -CONR 4 , X is -CR a -, and A is N or N-oxide can be prepared by the process described in the general scheme I.
  • Intermediate (14) can be synthesized by reduction of either intermediate (12) or (13) using the appropriate reducing conditions, such as hydrogenation in the presence of palladium on carbon, dissolving metal reductions (such as sodium in alcohol), or metal hydride reductions.
  • the intermediates of formula (12) and (13) can be obtained by cyclization of the intermediate of formula (11) using, for example, phosphorus oxychloride, aluminum chloride, or sulphuric acid.
  • the intermediate of formula (11) in turn, can be obtained by reacting an appropriately substituted alkoxy aniline of formula (10) (wherein FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group) with an appropriately substituted o-halobenzoic acid under appropriate basic conditions, such as with potassium carbonate in DMF in the presence of copper powder.
  • an appropriately substituted alkoxy aniline of formula (10) wherein FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group
  • the intermediate of formula (11) can be synthesized by reacting an appropriately substituted alkoxy aniline of formula (10) (wherein FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group) with an appropriately substituted diphenyl iodonium carboxylate, for example, in the presence of copper (II) acetate in DMF.
  • Intermediate (14) can be aromatized to intermediate (15) using oxidizing agents, such as DDQ or nitric acid.
  • the functional group (FG) on intermediate (15) can be then converted to the carboxylic acid intermediate (16) using known methods in the literature.
  • FG in intermediate (15) is an ester, it can be hydrolysed to the carboxylic acid; if FG is methyl then the methyl group can be oxidized using manganese or chromium reagents to the carboxylic acid group; if FG is a cyano group then the cyano group can be hydrolysed to the carboxylic acid; if FG is bromine then it can be transformed to carboxylic acid via lithiation followed by treatment with carbon dioxide.
  • the intermediate of formula (16) can then be converted to the desired compounds of formula (1) by reacting the acid halide, the mixed anhydride, or an active ester of the intermediate of formula (16) with an appropriate amine of the formula ArNHR 4 using standard conditions known in the literature such as sodium hydride in DMF, diisopropylethyl amine in THF and the like.
  • the desired compounds of formula (1) obtained can then be converted into their salts and/or the N-oxides and, if desired, salts of the compounds of formula (1)
  • the compounds of formula (1) wherein Y is -CONR 4 , X is -N or N-oxide and A is -CR a - can be prepared by the process described in the general scheme Ia.
  • Intermediate (21) can be synthesized by reduction of either intermediate (19) or (20) using the appropriate reducing conditions, such as hydrogenation (e.g., in the presence of palladium on carbon and the like), dissolving metal reductions (such as sodium in alcohol and the like), or metal hydride reduction.
  • the intermediates of formulas (19) and (20) can be obtained by cyclization of intermediate (18) using, for example, phosphorus oxychloride, aluminum chloride, or sulphuric acid.
  • the intermediate of formula (18) in turn can be obtained by reacting an appropriately substituted alkoxy aniline of formula (17) (wherein FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group) with an appropriately substituted o-halobenzoic acid under appropriate basic conditions, such as potassium carbonate in DMF in the presence of copper powder.
  • an appropriately substituted alkoxy aniline of formula (17) wherein FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group
  • the intermediate of formula (18) can be synthesized by reacting an appropriately substituted alkoxy aniline of formula (17) (wherein FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group) with an appropriately substituted diphenyl iodonium carboxylate, for example, in the presence of copper (II) acetate in DMF.
  • Intermediate (21) can be aromatized to intermediate (22) using oxidizing agents, such as DDQ or nitric acid.
  • the functional group (FG) on intermediate (22) can then be converted to the carboxylic acid intermediate (23) using known methods in the literature.
  • FG in intermediate (22) is an ester, it can be hydrolysed to the carboxylic acid; if FG is methyl then the methyl group can be oxidized using, for example, manganese or chromium reagents to the carboxylic acid group; if FG is a cyano group then the cyano group can be hydrolysed to the carboxylic acid; if FG is bromine then it can be transformed to carboxylic acid via lithiation followed by treatment with carbon dioxide.
  • the intermediate of the formula (22) can then be converted to the desired compounds of formula (1) by reacting the acid halide, the mixed anhydride, or an active ester of the intermediate of formula (22) with an appropriate amine of the formula ArNHR 4 using standard conditions known in the literature, such as sodium hydride in DMF, diisopropylethyl amine in THF and the like.
  • the desired compounds of formula (1) obtained can then be converted into their salts and/or the N-oxides and, if desired, salts of the compounds of formula (1) obtained can then be converted into the free compounds.
  • a A i iss O O,
  • intermediate (25) can be synthesized by reacting an appropriately substituted aromatic group of formula (24) (wherein FG is alkyl, acetyl formyl, cyano, halogen, nitro, amino, or a carboxylic acid ester group and Z is OH, SH or NHR 3 ) with an appropriately substituted o-halobenzoic acid under appropriate basic conditions, such as potassium carbonate in DMF in the presence of copper powder.
  • the intermediate of formula (25) can be further cyclized to the intermediate of formula (26) or (28).
  • the functional group (FG) on intermediate (26) or (28) can then be converted to a carboxylic acid group to obtain an intermediate of formula (27) or (29), respectively, using known methods in the literature.
  • FG in intermediates (26) and (28) is an ester, it can be hydrolysed to the carboxylic acid; if FG is methyl then the methyl group can be oxidized using, for example, manganese or chromium reagents to the carboxylic acid group; if FG is a cyano group then the cyano group can be hydrolysed to the carboxylic acid; if FG is bromine then it can be transformed to carboxylic acid via lithiation followed by treatment with carbon dioxide.)
  • the intermediate of formula (27) or (29) can then be converted to the desired compound of formula (1) by reacting the corresponding acid halide, the mixed anhydride, or an active ester of the intermediate of the formula (27) or (29) with an appropriate amine of the formula ArNHR 4 using standard conditions known in the literature, such
  • the appropriately functionalized nitroaromatic group of the general formula (30) (wherein FG is methyl, formyl, acetyl, cyano or an ester) can be reacted with appropriately substituted aniline of the formula (31), for example, in the presence of a base such as potassium hydroxide sodium hydroxide, to obtain the intermediate phenazine of formula (32).
  • the functional group FG in the intermediate of formula (32) can be converted to a carboxylic acid using standard processes (if FG is methyl, then it can be oxidized using oxidizing agents, such as chromium trioxide or potassium persulfate; if FG is an ester then it can be hydrolyzed, for example, using aqueous sodium hydroxide) to obtain the intermediate (33).
  • the intermediate of formula (33) can be converted to the desired compound of formula (1) by reacting the corresponding acid halide, the mixed anhydride, or an active ester of the intermediate of formula (33) with an appropriate amine of the formula ArNHR 4 using standard conditions known in the literature such as sodium hydride in DMF, diisopropylethyl amine in THF and the like.
  • the appropriately functionalized catechol of the formula (34) can be reacted with an appropriately substituted halonitrobenzene of the formula (35), for example, in the presence of base such as potassium hydroxide, sodium hydroxide, or potassium carbonate, to obtain the tricyclic intermediate of the formula (36).
  • base such as potassium hydroxide, sodium hydroxide, or potassium carbonate
  • Formylation using standard conditions, such as dichloromethylmethylether in the presence of tin (IV) chloride or phosphorus oxychloride in N,N-dimethylformamide can provide the intermediate (37).
  • This can be oxidized using oxidizing agents, such as sodium chlorite or potassium permanganate, to obtain the carboxylic acid intermediate (38).
  • the intermediate of formula (38) can be converted to the desired compound of formula (1) by reacting the corresponding acid halide, the mixed anhydride, or an active ester of the intermediate of the formula (38) with an appropriate amine of the formula ArNHR using standard conditions known in the literature, such as sodium hydride in DMF, diisopropylethyl amine in THF and the like.
  • the desired compound of formula (1) obtained can then be converted into their salts and/or the N-oxides and, if desired, salts of the compounds of formula (1) obtained can then be converted into the free compounds.
  • the N-oxidation can be carried out in a manner likewise familiar to the person of ordinary skill in the art, e.g., with the aid of m-chloroperoxybenzoic acid in dichloromethane at room temperature.
  • the substances according to the invention can be isolated and purified by any method known in the art, e.g., by distilling off the solvent in vacuum and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
  • Salts are obtained by dissolving the free compound in a suitable solvent, e.g., in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent e.g., in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basification or by acidifying into the free compounds which, in turn can be converted into salts.
  • the ethereal solvents used in the above described processes for the preparation of compounds of formula (1) are selected from diethyl ether, 1,2- dimethoxyethane, tetrahydrofuran, diisopropyl ether, 1,4 dioxane and the like.
  • the chlorinated solvent which may be employed may be selected from dichloromethane, 1,2-dichloroethane, chloroform, carbontetrachloride and the like.
  • the aromatic solvents which may be employed may be selected from benzene and toluene.
  • the alchoholic solvents which may be employed may be selected from methanol, ethanol, n-propanol, iso propanol, tert-butanol and the like.
  • the aprotic solvents which may be employed may be selected from N, N-dimethylformamide, dimethyl sulfoxide and the like.
  • the compounds prepared in the above described processes are obtained in pure form by using well known techniques such as crystallization using solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, water or their combinations, or column chromatography using alumina or silica gel and eluting the column with solvents such as hexane, petroleum ether (pet.ether), chloroform, ethyl acetate, acetone, methanol or their combinations.
  • solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, water or their combinations
  • solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichlorome
  • polymorphs of a compound of general formula (1) forming part of this invention may be prepared by crystallization of compound of formula (1) under different conditions, example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures, various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention provides new heterocyclic compounds of the general Formula 1, their analogs, tautomers, regioisomers, stereoisomers, enantiomers, diastreomers, polymorphs, pharmaceutically acceptable salts, appropriate N-oxides and pharmaceutically acceptable solvates and pharmaceutically acceptable salts of the preceeding.
  • the present invention also provides pharmaceutical compositions, containing compounds of general formula (1) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, enantiomers, diasteromers, or their pharmaceutically acceptable solvates and pharmaceutically acceptable salts of the preceeding in combination with the usual pharmaceutically employed carriers, diluents and the like.
  • the pharmaceutical compositions according to this invention can be used for the treatment of allergic disorders. It will be appreciated that some of the compounds of general formula (1) defined above according to the invention can contain one or more asymmetrically substituted carbon atoms.
  • the presence of one or more of these asymmetric centers in the compounds of general formula (1) can give rise to stereoisomers and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers and their mixtures, including racemic mixtures.
  • the invention may also contain E and Z geometrical isomers wherever possible in the compounds of general formula (1) which includes the single isomer or mixture of both the isomers
  • the pharmaceutical compositions may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like and may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • the active compounds of formula (1) will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds of formula (1) can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds of the formula (1) can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • injectable solutions or suspensions For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds of formula (1)
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the compounds can also be administered by inhalation when application within the respiratory tract is intended. Formulation of the present compounds is especially significant for respiratory inhalation, wherein the compound of Formula (1) is to be delivered in the form of an aerosol under pressure.
  • the compound of Formula (1) after it has been homogenised, e.g., in lactose, glucose, higher fatty acids, sodium salt of dioctylsulfosuccinic acid or, most preferably, in carboxymethyl cellulose, in order to achieve a microparticle size of 5 ⁇ m or less for the majority of particles.
  • the aerosol can be mixed with a gas or a liquid propellant for dispensing the active substance.
  • An inhaler or atomizer or nebulizer may be used.
  • Such devices are known. See, e.g., Newman et al., Thorax, 1985, 40:61-676; Berenberg, M., J.
  • the compound of the structure (1) for inhalation is preferably formulated in the form of a dry powder with micronized particles.
  • the compounds of the invention may also be used in a metered dose inhaler using methods disclosed in U.S. Patent 6, 131,566, incorporated herein by reference in their entirety.
  • the pharmaceutical compositions of the present invention may also contain or be co-administered with one or more known drugs selected from other clinically useful therapeutic agents.
  • MethyM-methoxy-acridine-l-carboxylate (480 mg, 1.81 mmol) was dissolved in methanol (15 ml). To this solution was added IN NaOH (1.0 ml) and stirred for 12 h at room temperature. The methanol was evaporated and the residue was diluted with water (20 ml), washed with ethyl acetate. The aqueous layer was neutralized to pH 4-
  • IR (KBr): 2965, 2846, 2878, 1728, 1623, 1529, 1462, 1350, 1261, 1200, 1158, 1061, 1020, 921, 883, 852, 810, 766, 672, 593.
  • Step 4 4-Methoxy phenazine -1-carboxylic acid l-Methoxy-4-methyl phenazine (1 equivalent) was dissolved in a mixture of acetic acid-water and to this, chromium trioxide (8.5 equivalent) was added and the resulting mixture was heated at 12O 0 C for 2h. After completion, the distillation of excess of acetic acid and water under reduced pressure followed by addition of water yielded the product as yellow colored crystalline solid.
  • Step 5 4-Nitrophenyl 4-methoxy-l-phenazine carboxylate
  • Step 2 4-methoxy-7-nitrooxanthrene-l-carboxylic acid To a solution of acetone water Methoxy-7-nitrooxanthrene- 1 -carbaldehyde (3.1 mmoles) and NH 2 SO 3 H (4.7 mmoles) was dissolved at 0-10 0 C under stirring. Slowly a solution OfNaO 2 Cl in water (4.7 mmoles) was added at 0- 10 0 C. Reaction completed within in 1-2 hrs. Acetone was distilled out and water was poured in reaction mass. The precipitated solid was filtered and dried.
  • Step 3 4-(difluoromethoxy) acridine-1-carboxylic acid To a solution of Methyl 4-(difluoromethoxy) acridine-1-carboxylate (700 mg, 2.32 mmol) in methanol (15 ml) was added a of IN solution of NaOH (5 ml) and heated at 70-80 0 C for 3 h.
  • Step 5 7V-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) acridine-1-carboxamide 4-nitrophenyl 4-(difluoromethoxy) acridine-1-carboxylate (150 mg, 0.367 mmol) and p-amino-3, 5, dichloropyridine (88.7 mg, 0.554 mmol) was dissolved in dry DMF and cooled to O 0 C.
  • PDE4 enzyme converts [ 3 H] cAMP to the corresponding [ 3 H] 5'- AMP in proportion to the amount of PDE4 present.
  • the [ 3 H] 5'-AMP then was quantitatively converted to free [ 3 H] adenosine and phosphate by the action of snake venom 5'-nucleotidase.
  • the amount of [ 3 H] adenosine liberated is proportional to PDE4 activity.
  • the assay was performed with modification of the method of Thompson and Appleman (Biochemistry; 1971; 10; 311-316) and Schwartz and Passoneau (Proc. Natl. Acad. Sci. U.S.A. 1974; 71; 3844-3848), both references incorporated herein by reference in their entirety, at 34 0 C.
  • the reaction mixture contained 12.5mM of Tris, 5 mM MgCl 2 , 1 ⁇ M cAMP (cold) and 3 H cAMP (0.1 uCi), (Amersham).
  • Stock solutions of the compounds to be investigated were prepared in DMSO in concentrations such that the DMSO content in the test samples did not exceed 0.05 % by volume to avoid affecting the PDE4 activity.
  • Drug samples were then added in the reaction mixture (25 ⁇ l/tube).
  • the assay was initiated by addition of enzyme mix (75 ⁇ l) and the mixture was incubated for 20 minutes at 34 0 C.
  • the reaction was stopped by boiling the tubes for 2 mins at 100 0 C in a water bath. After cooling on ice for 5 minutes and addition of 50 ug/reaction of 5'- nucleotidase snake venom from Crotalus atrox (Sigma) incubation was carried out again for 20 min. at 34 0 C.
  • the unreacted substrate was separated from ( 3 H) Adenosine by addition of Dowex AG 1-X8 ( Biorad Lab), (400 ul) which was prequilibrated (1:1 :1) in water and ethanol.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux inhibiteurs phosphodiestérase de type 4 (PDE4) de la formule (1) pour le traitement de l'asthme: Ar représente un aryle substitué ou non substitué, un arylalkyle substitué ou non substitué, un cycle hétérocyclique substitué ou non substitué, un cycle hétéroaryle substitué ou non substitué; chaque occurrence de L représente O, S ou NR3; X et A représentent indépendamment -CRaRb -, -CRa-, -C(=B)-, O, S(O)m, N ou NR3; chaque occurrence de m représente 0, 1 ou 2; n vaut 0-4; p vaut 0-2; Y représente -C(=B)C(=D)NR4 ou -C(=B)NR4 B représente O, S ou NRa; D représente O, S ou NRa. Les autres substituants sont définis dans les revendications.
PCT/IB2005/003031 2004-10-12 2005-10-11 Derives de 4-methoxyacridine-1-carboxamide et les analogues phenazine et oxanthrene utilises comme inhibiteurs pde4 pour le traitement de l'asthme et la maladie pulmonaire chronique (copd) Ceased WO2006040650A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US61819304P 2004-10-12 2004-10-12
US60/618,193 2004-10-12
IN1097MU2004 2004-10-14
IN1097/MUM/2004 2004-10-14

Publications (1)

Publication Number Publication Date
WO2006040650A1 true WO2006040650A1 (fr) 2006-04-20

Family

ID=35731358

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2005/003031 Ceased WO2006040650A1 (fr) 2004-10-12 2005-10-11 Derives de 4-methoxyacridine-1-carboxamide et les analogues phenazine et oxanthrene utilises comme inhibiteurs pde4 pour le traitement de l'asthme et la maladie pulmonaire chronique (copd)

Country Status (1)

Country Link
WO (1) WO2006040650A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20170042123A (ko) * 2015-10-08 2017-04-18 한국과학기술연구원 페나진 유도체를 포함하는 신경세포 보호용 조성물

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE50998C (de) * GESELLSCHAFT FÜR CHEMISCHE INDUSTRIE in Basel, Schweiz Verfahren zur Darstellung eines blauen Farbstoffes aus salzsaurem Nitrosodimethylanilin und dem krystallisirten Condensationsproduct aus Tannin und Anilin
EP0081338A1 (fr) * 1981-12-03 1983-06-15 Riker Laboratories, Incorporated N-(Tetrazolyl-5)phénazine-1-carboxamide
EP0205339A1 (fr) * 1985-06-10 1986-12-17 Warner-Lambert Company Phénazincarboxaldéhydes et leurs dérivés ayant une activité contre les microbes et contre les tumeurs
WO2004037805A1 (fr) * 2002-10-23 2004-05-06 Glenmark Pharmaceuticals Ltd. Nouveaux composes tricycliques utiles pour traiter les troubles inflammatoires et allergiques, procede de preparation de ces composes et compositions pharmaceutiques les contenant
WO2004069831A1 (fr) * 2003-02-10 2004-08-19 Glenmark Pharmaceuticals Ltd. Composes tricycliques utiles dans le traitement de troubles inflammatoires et allergiques, et procede de preparation de ces composes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE50998C (de) * GESELLSCHAFT FÜR CHEMISCHE INDUSTRIE in Basel, Schweiz Verfahren zur Darstellung eines blauen Farbstoffes aus salzsaurem Nitrosodimethylanilin und dem krystallisirten Condensationsproduct aus Tannin und Anilin
EP0081338A1 (fr) * 1981-12-03 1983-06-15 Riker Laboratories, Incorporated N-(Tetrazolyl-5)phénazine-1-carboxamide
EP0205339A1 (fr) * 1985-06-10 1986-12-17 Warner-Lambert Company Phénazincarboxaldéhydes et leurs dérivés ayant une activité contre les microbes et contre les tumeurs
WO2004037805A1 (fr) * 2002-10-23 2004-05-06 Glenmark Pharmaceuticals Ltd. Nouveaux composes tricycliques utiles pour traiter les troubles inflammatoires et allergiques, procede de preparation de ces composes et compositions pharmaceutiques les contenant
WO2004069831A1 (fr) * 2003-02-10 2004-08-19 Glenmark Pharmaceuticals Ltd. Composes tricycliques utiles dans le traitement de troubles inflammatoires et allergiques, et procede de preparation de ces composes

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20170042123A (ko) * 2015-10-08 2017-04-18 한국과학기술연구원 페나진 유도체를 포함하는 신경세포 보호용 조성물
KR101908454B1 (ko) 2015-10-08 2018-10-17 한국과학기술연구원 페나진 유도체를 포함하는 신경세포 보호용 조성물

Similar Documents

Publication Publication Date Title
EP1620429B1 (fr) Nouveaux composes heterocycliques pour le traitement des affections inflammatoires et allergiques, leur procede de preparation et compositions pharmaceutiques les contenant
CA2591438C (fr) Nouveaux composes heterocycliques utiles pour le traitement de troubles inflammatoires et allergiques
US7238725B2 (en) Tricyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
WO2004069831A1 (fr) Composes tricycliques utiles dans le traitement de troubles inflammatoires et allergiques, et procede de preparation de ces composes
WO2004111044A1 (fr) Composes tricycliques efficaces dans le traitement des affections inflammatoires et allergiques : leur procede de preparation
WO2006011024A2 (fr) Nouveaux composes tricycliques utilises dans le traitement de troubles inflammatoires et allergiques, procede de preparation associe, et compositions pharmaceutiques les contenant
WO2004016596A1 (fr) Composes condenses heterocycliques utilises comme inhibiteurs de pde-iv dans le traitement de troubles inflammatoires et allergiques
US7943634B2 (en) Substituted benzo[4,5]furo[3,2-c]pyridine derivatives as PDE 4 inhibitors
WO2006040650A1 (fr) Derives de 4-methoxyacridine-1-carboxamide et les analogues phenazine et oxanthrene utilises comme inhibiteurs pde4 pour le traitement de l'asthme et la maladie pulmonaire chronique (copd)
WO2006051390A1 (fr) Composes heterocycliques utilises pour le traitement de troubles inflammatoires et allergiques, compositions pharmaceutiques contenant ces composes et procedes permettant de les preparer
HK1111147B (en) Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders

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): BW GH 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: 05812618

Country of ref document: EP

Kind code of ref document: A1