US20030139417A1 - Cyclopropane CGRP antagonists, medicaments containing these compounds, and method for the production thereof - Google Patents

Cyclopropane CGRP antagonists, medicaments containing these compounds, and method for the production thereof Download PDF

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US20030139417A1
US20030139417A1 US10/121,872 US12187202A US2003139417A1 US 20030139417 A1 US20030139417 A1 US 20030139417A1 US 12187202 A US12187202 A US 12187202A US 2003139417 A1 US2003139417 A1 US 2003139417A1
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amino
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carbonyl
dihydro
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Wolfgang Eberlein
Wolfhard Engel
Klaus Rudolf
Henri Doods
Gerhard Hallermayer
Eckhart Bauer
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Boehringer Ingelheim Pharma GmbH and Co KG
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Assigned to BOEHRINGER INGELHEIM PHARMA KG reassignment BOEHRINGER INGELHEIM PHARMA KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HALLERMAYER, G., DOODS, H., RUDOLF, K., WNGEL, W., EBERLEIN, W., BAUER, E.
Publication of US20030139417A1 publication Critical patent/US20030139417A1/en
Priority to US11/169,078 priority Critical patent/US7407963B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to new cyclopropanes of general formula
  • R denotes a saturated or mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza, or S,S-dioxido-thiadiaza heterocyclic group
  • [0007] may contain one or two carbonyl groups adjacent to a nitrogen atom
  • [0008] may be substituted by an alkyl group at one of the nitrogen atoms
  • [0009] may be substituted at one or two carbon atoms by a straight-chain or branched alkyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl, or 1-methylimidazolyl group, whilst the substituents may be identical or different,
  • an olefinic double bond of one of the abovementioned unsaturated heterocyclic groups may be fused with a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methylpyrrole, quinoline, imidazole, or N-methylimidazole ring,
  • phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl, or 1-methylimidazolyl groups contained in R and the benzo-, thieno-, pyrido-, and diazino-fused heterocyclic groups in the carbon skeleton may additionally be mono-, di-, or trisubstituted by fluorine, chlorine, or bromine atoms, by alkyl, dialkylaminoalkoxy, nitro, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, phenyl, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxy,
  • R 1 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl, or isoquinolinyl group,
  • aromatic and heteroaromatic groups may additionally be mono-, di-, or trisubstituted in the carbon skeleton by fluorine, chlorine, or bromine atoms, by branched or unbranched alkyl groups, by cycloalkyl groups with 3 to 8 carbon atoms, by phenylalkyl, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, nitro, hydroxy, amino, acetylamino, propionylamino, methylsulfonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thi
  • hydroxy, amino, indolyl, and imidazolyl groups contained in the above-mentioned groups may be substituted by protecting groups familiar from peptide chemistry, preferably with the acetyl, benzyloxycarbonyl, or tert-butyloxycarbonyl group, and
  • all the abovementioned alkyl and alkoxy groups and the alkyl or alkylene moieties present within the other groups specified may contain 1 to 5 carbon atoms, unless otherwise stated.
  • protecting groups mentioned in the preceding definitions are meant the protecting groups familiar from peptide chemistry, especially
  • the present invention also includes the individual diastereomeric pairs of antipodes of general formula (I), the associated enantiomers and mixtures of the diastereomers and enantiomers which come under general formula (I).
  • racemates and enantiomers which come under general formula (I) and are trans-configured in relation to the cyclopropane ring.
  • the compounds of general formula (I) have valuable pharmacological properties, based on their selective CGRP-antagonistic properties.
  • the invention further relates to pharmaceutical compositions containing these compounds, their use, and the preparation thereof.
  • R denotes a mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, or thiaza heterocyclic group
  • [0031] may contain one or two carbonyl groups adjacent to a nitrogen atom
  • [0032] may be substituted at a carbon atom by a phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, or 1-methylpyrazolyl group,
  • phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, or 1-methylpyrazolyl groups contained in R and the benzo-, pyrido-, and diazino-fused heterocyclic groups in the carbon skeleton may additionally be mono-, di-, or trisubstituted by fluorine, chlorine, or bromine atoms, by alkyl, dialkylaminoalkoxy, nitro, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, [N-alkyl
  • alkoxy groups which may be substituted in the ⁇ -opposition by a 5- to 7-membered heteroalicyclic group, where the heteroalicyclic group is linked via a carbon or nitrogen atom and contains one or two heteroatoms not directly connected to each other selected from among oxygen and nitrogen,
  • R 1 denotes a phenyl, 1-naphthyl, or 2-naphthyl group
  • aromatic groups may be mono-, di-, or trisubstituted by fluorine, chlorine, or bromine atoms, by branched or unbranched alkyl groups, alkoxy, trifluoromethyl, nitro, hydroxy, amino, or acetylamino groups and the substituents may be identical or different,
  • R denotes a monounsaturated 5- to 7-membered diaza or triaza heterocyclic group
  • [0045] may contain a carbonyl group adjacent to a nitrogen atom
  • [0046] may be substituted at a carbon atom by a phenyl group, or
  • an olefinic double bond of one of the abovementioned unsaturated heterocyclic groups may be fused with a benzene, pyridine, or quinoline ring,
  • the phenyl groups contained in R as well as the benzo- and pyrido-fused heterocyclic groups in the carbon skeleton may additionally be mono-, di-, or trisubstituted by fluorine, chlorine, or bromine atoms, by alkyl, dialkylaminoalkoxy, nitro, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, carboxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, [N-alkyl-N-(dialkylaminoalkyl)-amino]carbonyl, [(hydroxycarbonylalkyl)amino]carbonyl, [(alkoxycarbonylalkyl)amino]carbonyl, alkanoyl, or trifluoromethoxy groups,
  • 5- to 7-membered alkyleneimino groups wherein a methylene group in the 3- or 4-position may be replaced by an oxygen atom or a methylimino group, for example, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-methyl-1,4-diazacyclohept-1-yl, or 4-morpholinyl groups,
  • alkoxy groups which may be substituted in the co-position by a 5- or 6-membered heteroalicyclic group, wherein the heteroalicyclic group is linked via a carbon atom and contains an oxygen atom in each of the 2- and 2′-positions or is linked via a carbon or nitrogen atom and contains one or two nitrogen atoms not directly linked to one another or an oxygen and a nitrogen atom which are separated from each other by at least one methylene group, for example, methoxy, ethoxy, propoxy, 2,5-dioxacyclopentylmethoxy, 2,6-dioxacyclohexylmethoxy, 2-(1-pyrrolidinyl)ethoxy, 2-(1-piperidinyl)ethoxy, 2-(4-methyl-1-piperazinyl)ethoxy, or 2-(4-morpholinyl)ethoxy groups,
  • R 1 denotes a phenyl group which may be mono-, di-, or trisubstituted by fluorine, chlorine, or bromine atoms, by alkoxy, trifluoromethyl, nitro, hydroxy, or amino groups, while the substituents may be identical or different,
  • R denotes a 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl, 3,4-dihydro-2(1H)-oxopyrido[4,3-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl, or 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl group,
  • the abovementioned mono- and bicyclic heterocyclic groups may be mono- or disubstituted in the carbon skeleton by fluorine, chlorine, or bromine atoms or may be monosubstituted by a 4-methyl-1-piperazinyl, 2,5-dioxacyclopentylmethoxy, methoxy, 2-(4-morpholinyl)ethoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, methoxycarbonylmethoxy, hydroxycarbonylmethoxy, nitro, trifluoromethyl, methoxycarbonyl, carboxy, hydroxy, aminocarbonyl, diethylaminocarbonyl, [N-(2-dimethylaminoethyl)-N-methylamino]carbonyl, [(methoxycarbonylmethyl)amino]carbonyl, or [(hydroxycarbonylmethyl)amino]carbonyl group,
  • R 1 denotes a phenyl group
  • [0059] which may be mono-, di-, or trisubstituted by fluorine, chlorine, or bromine atoms or by hydroxy or amino groups, wherein the substituents may be identical or different, for example, the 4-chlorophenyl, 4-amino-3,5-dibromophenyl, or 3,5-dibromo-4-hydroxyphenyl group,
  • R 1 is as hereinbefore defined
  • R is as hereinbefore defined.
  • the coupling is preferably carried out using methods known from peptide chemistry (cf., e.g., Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example, using carbodiimides such as, e.g., dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC), or ethyl-(3-dimethylaminopropyl)carbodiimide, or O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), tetrafluoroborate (TBTU), or 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP).
  • DCC dicyclohexylcarbodiimide
  • DI diisopropyl carbodiimide
  • any possible racemization can additionally be suppressed, if desired, or the reaction speed can be increased.
  • the couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between ⁇ 30° C. and +30° C., preferably ⁇ 20° C. and +25° C.
  • DIEA N-ethyldiisopropylamine
  • anhydride process is used as a further coupling method for synthesizing compounds of general formula (I) (cf. also: M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, pp. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, pp. 21-27).
  • the Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc.
  • R 1 is as hereinbefore defined
  • Nu denotes a leaving group, e.g., a halogen atom such as the chlorine, bromine, or iodine atom, an alkylsulfonyloxy group with 1 to 10 carbon atoms in the alkyl moiety, a phenylsulfonyloxy or naphthylsulfonyloxy group optionally mono-, di-, or trisubstituted by chlorine or bromine atoms, by methyl or nitro groups, whilst the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted by 1 or 2 methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4
  • R is as hereinbefore defined.
  • the reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e., the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between ⁇ 50° C. and +120° C., preferably ⁇ 10° C. and +30° C., and optionally in the presence of solvents.
  • the auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, e.g., sodium hydroxide, potassium hydroxide, or barium hydroxide, alkali metal carbonates, e.g., sodium carbonate, potassium carbonate, or cesium carbonate, alkali metal acetates, e.g., sodium or potassium acetate, as well as tertiary amines, e.g., pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyldiisopropylamine, N-ethyldicyclohexylamine, 1,4-diazabicyclo[2,2,2]octane, or 1,8-diazabicyclo[5,4,0]undec-7-ene, the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylform
  • R and R 1 are as hereinbefore defined.
  • the cyclopropanization may be carried out catalytically with diazomethane, using starting compounds of formula (V) in which the olefinic double bond is preferably (E)-configured.
  • the reaction is carried out at temperatures between 0° C. and +50° C., preferably at ambient temperature.
  • the preferred catalysts are palladium (II) compounds, for example, PdCl 2 (PhCN) 2 or palladium (II) acetate, Pd 3 (OAc) 6 .
  • Suitable solvents include inert ethers, for example, diethyl ether, hydrocarbons and most preferably chlorohydrocarbons such as dichloromethane or 1,2-dichloroethane, or mixtures of these solvents (cf. also: H. Abdallah, R. Green, and R. Carrie, Tetrahedron Letters 23, 503-506 (1982)).
  • the cyclopropanization of (E)-configured compounds of general formula (V) can also be made asymmetric by using the semicorrin copper catalysts described by A. Pfaltz, Acc. Chem. Res. 26, 339-345 (1993), thereby obtaining a high enantiomeric excess.
  • the diazomethane required may also be produced in situ, by adding N-methyl-N-nitrosourea batchwise to a mixture of an alkene of general formula (V), the palladium catalyst, the organic solvent, and 40% to 50% aqueous potassium hydroxide solution; with this method, at most 2 moles of N-methyl-N-nitrosourea are generally needed per mol of the alkene of general formula (V).
  • the cyclopropanization of alkenes of general formula (V) wherein the olefinic double bond may be in any orientation, but preferably the (E)-configuration may be carried out analogously to the so-called Simmons-Smith reaction with diiodomethane and the zinc/copper pair (cf. also: Simmons, Cairns, Vladuchik, and Hoiness, Org. React. 20, 1-131 (1973); Furukawa and Kawabata, Adv. Organomet. Chem. 12, 83-134 (1974)) or the zinc/silver pair (cf. also: J. M. Denis, C. Girard, and J. M. Conia, Synthesis 1972, 549).
  • Simmons-Smith reaction with diiodomethane and the zinc/copper pair cf. also: Simmons, Cairns, Vladuchik, and Hoiness, Org. React. 20, 1-131 (1973); Furukawa and Kawabata, Adv. Organomet. Chem. 12,
  • the zinc/copper pair can be produced by numerous alternative methods (cf., for example, Shank and Shechter, J. Org. Chem. 24, 1525 (1959); LeGoff, J. Org. Chem. 29, 2048 (1964)), of which the heating of zinc powder with copper (I) chloride in diethyl ether and under nitrogen (Rawson and Harrison, J. Org. Chem. 35, 2057 (1970)) is particularly suitable.
  • the reaction also works with non-activated zinc in an ultrasound bath (cf. also: Repi and Vogt, Tetrahedron Letters 23, 2729 (1982); Repi, Lee, and Giger, Org. Prep. Proced. Int. 16, 25 (1984).
  • the species attacking the alkene of general formula (V) is an organozinc compound which occurs as an intermediate, bis-(iodomethyl)-zinc (cf. also: Georg Wittig and Frank Wingler, Chem. Ber. 97, 2146 (1964)) or the adduct (ICH 2 ) 2 Zn—ZnI 2 (Blanchard and Simmons, J. Am. Chem. Soc. 86, 1337 (1964)), the solutions of which are sufficiently stable for physicochemical investigations.
  • the cyclopropanization takes place stereospecifically syn.
  • the reactivity of the reagent can be increased by the addition of a Lewis acid, for example, nickel(II) bromide (cf also: H. Kanai et al., Bull.
  • the substrate of general formula (V) is reacted with diiodomethane or another dihalomethane and diethylzinc (cf. also: Furukawa, Kawabata and Nishimura, Tetrahedron 24, 53 (1968), Tetrahedron Letters 1968, 3495; Nishimura, Kawabata, and Furukawa, Tetrahedron 25, 2647 (1969); Miyano and Hashimoto, Bull. Chem. Soc. Jpn.
  • the reagent required may also be produced from dihalomethanes and copper (Kawabata, Kamemura, and Naka, J. Am. Chem. Soc. 101, 2139 (1979); Kawabata, Tanimoto, and Fujiwara, Tetrahedron 35, 1919 (1979)).
  • the cyclopropanization is carried out at temperatures between 0° C. and +70° C., preferably at ambient temperature, and using ethereal solvents, for example, diethyl ether or tetrahydrofuran.
  • R 2 denotes the methyl or ethyl group.
  • the reaction is carried out in dipolar aprotic solvents, preferably in dimethylsulfoxide, and at temperatures between +10° C. and +80° C., preferably +20° C. and +60° C.
  • the oxosulfonium ylides VI and VII may be put in as such but are also produced in situ from the trimethyloxosulfonium iodide of formula
  • R 2 is as hereinbefore defined, by the action of sodium hydride (cf. also: C. R. Johnson, E. R. Janiga, and M. Haake, J. Am. Chem. Soc. 90, 3890 (1968); C. R. Johnson and C. W. Schroeck, J. Am. Chem. Soc. 90, 6852 (1968); C. R. Johnson and G. F. Katekar, J. Am. Chem. Soc. 92, 5753 (1970); C. R. Johnson, M. Haake, and C. W. Schroeck, J. Am. Chem. Soc. 92, 6594 (1970); C. R. Johnson and P. E. Rogers, J. Org. Chem. 38, 1793 (1973) in dimethylsulfoxide.
  • Ylides of general formula (VII) can also be obtained in optically active form and are thus suitable for the asymmetric synthesis of compounds of general formula (I).
  • R 1 and R 1a have the meanings given above for R and R 1 , respectively, with the proviso that at least one of these groups contains one or more alkoxycarbonyl groups,
  • alkaline saponification of the esters of general formula (Ia) lithium hydroxide, sodium hydroxide, and potassium hydroxide are preferred; however, other alkali metal hydroxides such as cesium hydroxide, or alkaline earth metal hydroxides, for example, barium hydroxide, or tetraalkylammonium hydroxides are also suitable.
  • the procedure is carried out in aqueous solution and advantageously with the addition of water-miscible co-solvents, preferably alcohols such as methanol, ethanol or 2-ethoxyethanol, or ethers such as tetrahydrofuran or 1,4-dioxane.
  • Suitable temperatures for alkaline saponification are between ⁇ 10° C.
  • Dilute aqueous organic or inorganic acids e.g., acetic acid, oxalic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, and phosphoric acid are suitable for liberating the basic carboxylic acids from the salts thereof initially formed.
  • R 1 is as hereinbefore defined
  • the group R b has the meanings given for R hereinbefore, with the proviso that it is mono-, di-, or trisubstituted in the carbon skeleton by the carboxy group,
  • alkylamines N-alkyl-N-(dialkylaminoalkyl)amines, hydroxycarbonylalkylamines, alkoxycarbonylalkylamines, or dialkylamines, for example, 1-methylpiperazine, morpholine, pyrrolidine, piperidine, or hexahydroazepine.
  • the coupling is preferably carried out using methods known from peptide chemistry (cf., e.g., Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example, using carbodiimides such as, e.g., dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC), or ethyl-(3-dimethylaminopropyl)carbodiimide, or O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), tetrafluoroborate (TBTU), or 1H-benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP).
  • DCC dicyclohexylcarbodiimide
  • DI diisopropyl carbodiimide
  • any possible racemization can additionally be suppressed, if desired, or the reaction speed can be increased.
  • the couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between ⁇ 30° C. and +30° C., preferably ⁇ 20° C. and +25° C.
  • DIEA N-ethyldiisopropylamine
  • anhydride process is used as a further coupling method for synthesizing compounds of general formula (I) (see also: M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, pp. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, pp. 21-27).
  • the Vaughan variant of the mixed anhydride process is preferred (J. R. Vaughan Jr., J. Amer. Chem. Soc.
  • the new cyclopropanes of general formula (I) according to the invention contain at least one chiral centre. Occasionally, the compounds may occur in the form of two diastereomeric pairs of antipodes.
  • the invention includes the individual isomers and the mixtures thereof.
  • the diastereomers may be separated on the basis of their different physico-chemical properties, e.g., by fractional crystallization from suitable solvents, by high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.
  • Racemates covered by general formula (I) may be separated, for example, by HPLC on suitable chiral stationary phases (e.g., Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example, (+)- or ( ⁇ )-tartaric acid, (+)- or ( ⁇ )-diacetyl tartaric acid, (+)- or ( ⁇ )-monomethyl tartrate, or (+)-camphorsulfonic acid, or an optically active base, for example, with (R)-(+)-1-phenylethylamine, (S)-( ⁇ )-1-phenylethylamine, or (S)-brucine.
  • an optically active acid for example, (+)- or ( ⁇ )-tartaric acid, (+)- or ( ⁇ )-diacetyl tartaric acid, (+)- or ( ⁇ )-monomethyl tartrate, or
  • the racemate of a compound of general formula (I) is reacted with one of the abovementioned optically active acids or bases in equimolar amounts in a solvent and the resulting crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities.
  • This reaction may be carried out in any type of solvent provided that it is sufficiently different in terms of the solubility of the salts.
  • methanol, ethanol, or mixtures thereof, for example, in a ratio by volume of 50:50, are used.
  • each of the optically active salts is dissolved in water, neutralized with a base such as sodium carbonate, potassium carbonate, sodium hydroxide solution, or potassium hydroxide solution and in this way the corresponding free compound is obtained in the (+) or ( ⁇ ) form.
  • a base such as sodium carbonate, potassium carbonate, sodium hydroxide solution, or potassium hydroxide solution
  • the (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds covered by general formula (I) may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration.
  • the starting compounds of general formula (Ia) and (Ib) may be prepared by methods a) to c) described in this application.
  • the starting materials of general formula (II) required for the synthesis of the compounds of general formula (I) may easily be prepared, for example, from the corresponding carboxylic acid esters, such as the methyl or ethyl esters, by saponification with aqueous lithium, sodium, or potassium hydroxide solution followed by acidification with hydrochloric acid analogously to methods known in the art.
  • the carboxylates required for this may be obtained from the corresponding 4-aryl- or hetaryl-4-oxo-2-butenoates, for example, by reacting with dimethyloxosulfonium methylide analogously to the process described in c) above.
  • 4-aryl- or hetaryl-4-oxo-2-butenoates are either known from the literature or may easily be obtained from 4-aryl- or hetaryl-4-oxo-2-butenoic acids known from the literature (cf. also published German applications 2 047 806 and 2 103 749).
  • Secondary amines of general formula (III) are either known or may be synthesized, for example, analogously to processes described in WO 98/11128.
  • Starting compounds of general formula (IV) may be obtained from the starting compounds of general formula (II) by current methods.
  • the starting compounds of general formula (V) may easily be prepared, for example, by acylating compounds of formula (III) with unsaturated carboxylic acid derivatives.
  • the compounds of general formula (I) obtained may, if they contain suitable basic functions, be converted, particularly for pharmaceutical use, into their physiologically acceptable salts with inorganic or organic acids.
  • Suitable acids include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid, or maleic acid.
  • the new compounds of formula (I), if they contain an acid function, for example, a carboxy group, may if desired be converted into the addition salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable addition salts thereof.
  • Suitable bases for this include, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine, and triethanolamine.
  • the new compounds of general formula (I) and the physiologically acceptable salts thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP receptor binding studies.
  • the compounds display CGRP-antagonistic properties in the pharmacological test systems described hereinafter.
  • SK-N-MC cells are cultivated in “Dulbecco's modified Eagle medium”. The medium is removed from confluent cultures. The cells are washed twice with PBS buffer (Gibco 041-04190 M), detached by the addition of PBS buffer, mixed with 0.02% EDTA, then detached again and isolated by centrifuging.
  • PBS buffer Gibco 041-04190 M
  • BSS “Balanced Salts Solution”
  • NaCl 120, KCl 5.4, NaHCO 3 16.2, MgSO 4 0.8, NaHPO 4 1.0, CaCl 2 1.8, D-glucose 5.5, HEPES 30, pH 7.40 the cells are centrifuged twice at 100 ⁇ g and resuspended in BSS. After the number of cells has been determined, the cells are homogenized using an Ultra-Turrax and centrifuged for 10 minutes at 3000 ⁇ g.
  • the supernatant is discarded and the pellet is recentrifuged in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40), enriched with 1% bovine serum albumin and 0.1% bacitracin) and resuspended (1 mL/1000000 cells).
  • Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40), enriched with 1% bovine serum albumin and 0.1% bacitracin) and resuspended (1 mL/1000000 cells).
  • the homogenized product is frozen at ⁇ 80° C.
  • the membrane preparations are stable for more than 6 weeks under these conditions.
  • the homogenized product is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40) and homogenized for 30 seconds with an Ultra-Turrax. 230 ⁇ L of the homogenized product are incubated for 180 minutes at ambient temperature with 50 pM 125 1-iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham) and increasing concentrations of the test substances in a total volume of 250 ⁇ L. The incubation is ended by rapid filtration through GF/B-glass fibre filters treated with polyethyleneimine (0.1%) using a cell harvester. The protein-bound radioactivity is measured using a gamma counter. Non-specific binding is defined as the bound radioactivity in the presence of 1 ⁇ M human CGRP-alpha during incubation.
  • assay buffer 50 mM Tris, 150 mM NaCl, 5 mM M
  • concentration binding curves are analyzed using computer-aided non-linear curve matching.
  • SK-N-MC cells (1 million cells) are washed twice with 250 ⁇ l incubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated at 37° C. for 15 minutes. After the addition of CGRP (10 ⁇ L) as agonist in increasing concentrations (10 ⁇ 11 to 10 ⁇ 6 M), or additionally the substance in 3 to 4 different concentrations, the mixture is incubated for another 15 minutes.
  • Intracellular cAMP is then extracted by the addition of 20 ⁇ L of 1M HCl and centrifugation (2000 ⁇ g, 4° C., for 15 minutes). The supernatants are frozen in liquid nitrogen and stored at ⁇ 20° C.
  • cAMP contents of the samples are determined by radioimmunoassay (Amersham) and the pA 2 values of antagonistically acting substances are determined graphically.
  • the compounds of general formula (I) exhibit CGRP-antagonistic properties in the in vitro test model described, in a dosage range of between 10 ⁇ 11 to 10 ⁇ 5 M.
  • the compounds of general formula (I) and the salts thereof with physiologically acceptable acids or bases are thus suitable for the acute and prophylactic treatment of headaches, particularly migraine or cluster headaches.
  • the compounds of general formula (I) also have a positive effect on the following diseases: non-insulin-dependent diabetes mellitus (“NIDDM”), cardiovascular diseases, morphine tolerance, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g., inflammatory diseases of the joints (arthritis), inflammatory lung diseases, allergic rhinitis, asthma, diseases accompanied by excessive vasodilatation and consequent reduced circulation of blood through the tissues, e.g., shock and sepsis.
  • NIDDM non-insulin-dependent diabetes mellitus
  • cardiovascular diseases e.g., morphine tolerance
  • skin diseases particularly thermal and radiation-induced skin damage including sunburn
  • inflammatory diseases e.g., inflammatory diseases of the joints (arthritis)
  • inflammatory lung diseases e.g., allergic
  • the symptoms of menopausal hot flushes in oestrogen-deficient women caused by vasodilatation and increased blood flow are favorably affected by the CGRP-antagonists of the present application in a preventive and acute-therapeutic capacity, this therapeutic approach being distinguished from hormone replacement by the absence of side effects. Furthermore, the compounds of general formula (I) have an alleviating effect on pain in general.
  • the dosage required to achieve a corresponding effect is conveniently 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5 mg/kg of body weight, when administered intravenously or subcutaneously and 0.01 to 50 mg/kg of body weight, preferably 0.1 to 30 mg/kg of body weight when administered orally, nasally, or by inhalation, 1 to 3 ⁇ a day in each case.
  • the compounds of general formula (I) prepared according to the invention optionally combined with other active substances such as, e.g., antiemetics, prokinetics, neuroleptics, antidepressants, neurokinine antagonists, anticonvulsants, histamine-H1 receptor antagonists, antimuscarinics, ⁇ -blockers, ⁇ -agonists, and ⁇ -antagonists, ergot alkaloids, mild analgesics, non-steroidal antiinflammatories, corticosteroids, calcium antagonists, 5-HT 1D agonists or other anti-migraine agents, together with one or more inert conventional carriers and/or diluents, e.g., with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propy
  • active substances such as,
  • the active substances which may be used for the abovementioned combinations thus include, for example, meloxicam, ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, propranolol, nadolol, atenolol, clonidine, indoramine, carbamazepine, phenytoin, valproate, amitriptyline, lidocaine, diltiazem, or sumatriptan and other 5-HT1D-agonists such as, for example, naratriptan, zolmitriptan, avitriptan, rizatriptan and eletriptan.
  • the dosage of these active substances is expediently 1/5 of the lowest recommended dose to 1/1 of the normally recommended dose, i.e.
  • the invention further relates to the use of the compounds of general formula (I) as valuable adjuvants for the production and purification (by affinity chromatography) of antibodies as well as, after suitable radioactive labeling, for example, by direct labeling With 125 I or 131 I or by tritiation of suitable precursors, for example, by replacing halogen atoms with tritium, in RIA and ELISA assays and as a diagnostic or analytical adjuvant in neurotransmitter research.
  • suitable radioactive labeling for example, by direct labeling With 125 I or 131 I or by tritiation of suitable precursors, for example, by replacing halogen atoms with tritium, in RIA and ELISA assays and as a diagnostic or analytical adjuvant in neurotransmitter research.
  • TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
  • CDT 1,1′-carbonyldi-(1,2,4-triazole)
  • PE petroleum ether
  • reaction mixture was stirred into a mixture of 500 g of crushed ice and 60 mL of concentrated hydrochloric acid, the precipitate was suction filtered, washed thoroughly with water and dried over Siccapent in a vacuum drying chamber at a temperature of 50° C. 7.8 g (87% of theoretical) of colorless crystals were obtained, m.p. 150° C.-153° C.
  • N B C Remarks % yield El R f IR [cm ⁇ 1 ] N8 H — from N8-CH 2 Ph, H 2 , 10% Pd—C, MeOH 92 D 0.23 1665 (C ⁇ O) N18 H — from N18-CH 2 Ph, H 2 , Pd(OH) 2 , MeOH 81 D 0.26 N19 H — from N19-CH 2 Ph, H 2 , Pd(OH) 2 , MeOH 85 N21 H — from N21-CH 2 Ph, H 2 , Pd(OH) 2 , MeOH 100 D 0.27 N23 H — from N23-CH 2 Ph, H 2 , Pd(OH) 2 , MeOH 74 D 0.35
  • the residue obtained was purified by column chromatography on silica gel using dichloromethane/methanol 9/1 (v/v) to start with, then dichloromethane/methanol/concentrated ammonia 70/30/3 (v/v/v) as eluant.
  • the appropriate fractions were evaporated down in vacuo, the residue remaining (0.5 g; 59% of theoretical) was used in the next step without further purification.
  • composition 1 capsule for powder inhalation contains: active ingredient 1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 mg 71.0 mg
  • the active ingredient is ground to the particle size required for inhaled substances.
  • the ground active ingredient is homogeneously mixed with lactose. The mixture is transferred into hard gelatine capsules.
  • Composition 1 puff contains: active ingredient 1.0 mg benzalkonium chloride 0.002 mg disodium edetate 0.0075 mg purified water ad 15.0 ⁇ L
  • composition 1 vial contains: active ingredient 0.1 g sodium chloride 0.18 g benzalkonium chloride 0.002 g purified water ad 20.0 mL
  • Composition 1 puff contains: active ingredient 1.0 mg lecithin 0.1% propellant gas ad 50.0 ⁇ L
  • micronised active ingredient is homogeneously suspended in the mixture of lecithin and propellant gas.
  • the suspension is transferred into a pressurised container with a metering valve.
  • composition active ingredient 1.0 mg sodium chloride 0.9 mg benzalkonium chloride 0.025 mg disodium edetate 0.05 mg purified water ad 0.1 mL
  • the active ingredient and the excipients are dissolved in water and transferred into a suitable container.
  • composition active substance 5 mg glucose 250 mg human serum albumin 10 mg glycofurol 250 mg water for injections ad 5 mL
  • WfI water for injections
  • human serum albumin is added
  • active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into ampoules under nitrogen gas.
  • composition active substance 100 mg monopotassium dihydrogen phosphate (KH 2 PO 4 ) 12 mg disodium hydrogen phosphate (Na 2 HPO 4 .2H 2 O) 2 mg sodium chloride 180 mg human serum albumin 50 mg Polysorbate 80 20 mg water for injections ad 20 mL
  • Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate, and disodium hydrogen phosphate are dissolved in water for injections (WfI); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into ampoules.
  • composition active substance 10 mg mannitol 300 mg human serum albumin 20 mg
  • Mannitol is dissolved in water for injections (WfI); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into vials; freeze-dried.
  • Solvent for lyophilisate Polysorbate 80 (Tween 80) 20 mg mannitol 200 mg water for injections ad 10 mL
  • Polysorbate 80 and mannitol are dissolved in water for injections (WfI); transferred into ampoules.
  • composition active substance 20 mg lactose 120 mg maize starch 40 mg magnesium stearate 2 mg Povidon K 25 18 mg
  • Active substance, lactose, and maize starch are homogeneously mixed; granulated with an aqueous solution of Povidone; mixed with magnesium stearate; compressed in a tablet press; weight of tablet 200 mg.
  • composition active substance 20 mg maize starch 80 mg highly dispersed silica 5 mg magnesium stearate 2.5 mg
  • Active substance, maize starch, and silica are homogeneously mixed; mixed with magnesium stearate; the mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.
  • composition active substance 50 mg hard fat (Adeps solidus) q.s. ad 1700 mg
  • Hard fat is melted at about 38° C.; ground active substance is homogeneously dispersed in the molten hard fat; after cooling to about 35° C. it is poured into chilled molds.
  • composition active substance 10 mg mannitol 50 mg human serum albumin 10 mg water for injections ad 1 mL
  • Mannitol is dissolved in water for injections (WfI); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with WfI; transferred into ampoules under nitrogen gas.

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US20060122250A1 (en) * 2004-12-03 2006-06-08 Chaturvedula Prasad V Novel processes for the preparation of CGRP-receptor antagonists and intermediates thereof
US20060229447A1 (en) * 2004-11-03 2006-10-12 Chaturvedula Prasad V Constrained compounds as CGRP-receptor antagonists
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WO2009034029A2 (de) * 2007-09-07 2009-03-19 Boehringer Ingelheim International Gmbh 1-substituierte 4 -heterocyclylpiperidine als cgrp antagonisten
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US9315449B2 (en) 2008-05-15 2016-04-19 Duke University Substituted pyrazoles as heat shock transcription factor activators
UA105182C2 (ru) 2008-07-03 2014-04-25 Ньюрексон, Інк. Бензоксазины, бензотиазины и родственные соединения, которые имеют ингибирующую nos активность
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DE19952147A1 (de) 2001-05-03
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ATE301117T1 (de) 2005-08-15
EA005137B1 (ru) 2004-12-30
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CA2387134A1 (en) 2001-05-10
KR20020047290A (ko) 2002-06-21
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JP2003513087A (ja) 2003-04-08
EP1228059A1 (de) 2002-08-07
YU30902A (sh) 2005-07-19
US20050267137A1 (en) 2005-12-01
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US7407963B2 (en) 2008-08-05

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