EP1778691A1 - Hydrate und polymorphe des 4-[[(7r)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl|]amino]-3-methoxy-n-(1-methyl-4-piperidinyl)-benzamid, verfahren zu deren herstellung und deren verwendung als arzneimittel - Google Patents

Hydrate und polymorphe des 4-[[(7r)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl|]amino]-3-methoxy-n-(1-methyl-4-piperidinyl)-benzamid, verfahren zu deren herstellung und deren verwendung als arzneimittel

Info

Publication number
EP1778691A1
EP1778691A1 EP05772062A EP05772062A EP1778691A1 EP 1778691 A1 EP1778691 A1 EP 1778691A1 EP 05772062 A EP05772062 A EP 05772062A EP 05772062 A EP05772062 A EP 05772062A EP 1778691 A1 EP1778691 A1 EP 1778691A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
anhydrate
preparation
methyl
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.)
Withdrawn
Application number
EP05772062A
Other languages
German (de)
English (en)
French (fr)
Inventor
Guenter Linz
Peter Sieger
Gerd F. Kraemer
Werner Rall
Rolf Herter
Matthias Hoffmann
Rolf Schmid
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.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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
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Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Priority to EP05772062A priority Critical patent/EP1778691A1/de
Publication of EP1778691A1 publication Critical patent/EP1778691A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems

Definitions

  • the present invention relates to new hydrates and new polymorphs of 4 - [[(7i?) - 8-cyclopentyl-T-S-ethyl ⁇ j ⁇ J -tetrahydro-S-methyl- ⁇ -oxo-l-pteridinyllaminoJ-S-methoxy- N- (1-methyl-4-piperidmyl) benzamide, process for their preparation and their use as pharmaceuticals.
  • the compound 4 - [[(7i) - 8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-olpteridyl] amino] -3-methoxy-N - (1-methyl-4-piperidinyl) benzamide has the structure of the following formula (I).
  • the present invention provides novel hydrates and novel polymorphic forms of the compound of formula (I) having antiproliferative activity.
  • Another object of the invention is the anhydrate of the compound of formula (I).
  • Another object of the invention is a pharmaceutical composition which contains a therapeutically effective amount of one of the above-described hydrates and polymorphic forms of the compound of formula (I) and one or more pharmaceutically acceptable excipients. Boehringer Ingelheim - 3 - 1-1758-out
  • the invention furthermore relates to the hydrates and polymorphic forms of the compound of the formula (I) according to the invention for use as medicaments having an antiproliferative action.
  • Another object of the invention is the use of hydrates and polymorphic forms of the compound of formula (I) according to the invention for the manufacture of a medicament for the treatment and / or prevention of cancer, infections, inflammatory and autoimmune diseases.
  • Another object of the invention is the use of the erfmdungshielen
  • Another object of the invention is a process for the preparation of the compound of formula (I), characterized in that a compound of formula 4
  • Another object of the invention is a process for the preparation of a compound of formula 9,
  • Another object of the invention is a compound of formula 3
  • the invention further provides a process for preparing the monohydrate of the compound of the formula (I), which comprises the following process steps:
  • Another object of the invention is a process for preparing the trihydrate of the compound of formula (I), wherein the monohydrate of the compound of formula (I) is exposed to a relative humidity of at least 70%.
  • Another object of the invention is a process for the preparation of the anhydrate form III of the compound of formula (I), wherein:
  • the monohydrate of the compound of formula (I) is exposed to a temperature of about 70 ° C, preferably 70 to 120 ° C, more preferably 70 to 90 ° C.
  • Another object of the invention is a process for the preparation of the anhydrate Form I of the compound of formula (I), wherein the anhydrate Form III of the compound of formula (I) is melted and then the melt at a temperature of at least 140 ° C, preferably from 140 ° C to 160 0 C, is crystallized.
  • the invention further provides a process for preparing the anhydrate Form I of the compound of the formula (I) comprising the following process steps: a) Preparation of a solution of the compound of the formula (I) in a solvent mixture of ethyl acetate and methyl tert-butyl ether , preferably in the ratio of ethyl acetate / methyl tert-butyl ether of 3: 5 (v / v) or from a
  • the invention further provides a process for preparing the anhydrate Form II of the compound of the formula (I) comprising the following process steps: a) preparation of a solution of the compound of the formula (I) in ethyl acetate, b) crystallization of the anhydrate Form II of the compound of the formula (I) from ethyl acetate with subsequent addition of diethyl ether and c) isolation of the anhydrate Form II of the compound of the formula (I).
  • the invention further provides a process for preparing the anhydrate Form I of the compound of the formula (I) comprising the following process steps: a) melting the anhydrate Form II of the compound of the formula (I), b) crystallizing the melt at a temperature of at least 185 0 C, preferably at a temperature of 185 to 200 ° C.
  • the organic phase is separated off and the product-containing water phase is transferred back into the reactor. It is rinsed with 4 L of water. Under reduced pressure, 3.2 L of water are distilled off at 50 ° C. To the remaining solution is allowed at 4O 0 C 4.87 kg (60.9 mol) sodium hydroxide sol. Accrue (50%). It is rinsed with 4 L of water. The product suspension is allowed to cool to 22 ° C and stirred for 30 min. At this temperature. The suspension is filtered off with suction and the filter cake is washed with 40 L of water. The product is dried in a vacuum drying cabinet at 4O 0 C. This gives 5.65 kg of product.
  • the filtrate is transferred to a reactor and rinsed the transport vessel with 5 L demineralized water.
  • the reactor contents are heated to 5O 0 C.
  • a mixture of 5.45 kg (68.2 mol) of sodium hydroxide solution is added. (50%, techn.) And 7 L of demineralised water too.
  • the mixture is stirred for 10 minutes at 45-50 ° C.
  • the suspension is cooled to 20 ° C and stirred for 1-1.5 hours at this temperature.
  • the product is filtered off, washed with 30 L demineralized water and dried at 45 ° C in a vacuum oven. 4.13 kg of product 4 are obtained.
  • the preparation of the methyl ester 6a, the ethyl ester 6b and the 2-propyl ester 6c is carried out according to literature known regulations, for example according to WO 03/020722.
  • the tert-butyl ester 6d is prepared by transesterification with tert-butyl acetate in the presence of perchloric acid (J. Med. Chem., Vol. 37, No. 20, 1994, 3294-3302).
  • the amino acids can be used in the form of the bases or as hydrochlorides in the subsequent nucleophilic substitution reaction.
  • Amino acid amide 6e is prepared by aminolysis of methyl ester 6a with 40% aqueous methylamine solution at room temperature.
  • Amino acid amide 6f is prepared by amidation of the free amino acid with a five-fold excess of 2 molar dimethylamine solution in tetrahydrofuran in the presence of O- (benzotriazol-1-yl) -N, N, N ', N'-
  • lipophilic solvents such as cyclohexane, methylcyclohexane, toluene and mixtures thereof are particularly suitable
  • the compounds 7b-f are prepared.
  • a more polar solvent e.g. Ethyl acetate or dichloromethane.
  • the catalyst was filtered off and the hydrogenation solution was evaporated under reduced pressure.
  • To the residue are added 4 L of demineralized water and 4 L of ethyl acetate. Between the phases, a precipitate forms, which contains product.
  • the aqueous phase is separated off. 2 liters of ethyl acetate are added to the organic phase and the precipitate is filtered off with suction.
  • the precipitate is suspended in 600 mL of demineralized water, stirred for 1 hour at room temperature, suction filtered and washed with demineralised water. This gives HO g of moist product A.
  • Dimethylacetamide is added at 4-1O 0 C in portions within one hour 38 g (0.95 mol) of sodium hydride (60 percent dispersion in mineral oil). Remove the cooling bath Boehringer Ingelheim - 14 - 1-1758-out
  • a suspension of 100 g (356 mmol) of 8 and 73.8 g (534 mmol) of potassium carbonate in 400 ml of dimethyl carbonate is heated to 130 ° C. in an autoclave for 6 hours. It is allowed to cool and 300 ml of demineralized water and 200 ml of ethyl acetate are added with stirring. The aqueous phase is separated together with undissolved salts. Are mbar at a pressure of 180 from the organic phase and a bath temperature of 70 0 C distilled off 500 ml of solvent. To the residue is added 600 mL of demineralized water and distilled at a pressure of 150 mbar and a heating bath temperature of 80 0 C 100 mL of solvent.
  • a suspension of 201 g (1.06 mol) of para-toluenesulfonic acid hydrate, 209 g (706 mmol) of 9 and 183 g (695 mmol) of 4 in 800 mL of 2-methyl-4-pentanol is heated to reflux. 100 ml of solvent are distilled off. The mixture is refluxed for 3 hours, 200 ml of 2-methyl-4-pentanol are added and distilled off 120 ml of solvent. After heating for 2 hours under reflux, a further 280 ml of solvent are distilled off. It is allowed to cool to 100 ° C and to the reaction solution 1 L demineralized water and then 0.5 L ethyl acetate.
  • the organic phase is separated and the aqueous phase washed again with 0.5 L ethyl acetate.
  • aqueous phase are added 1.5 L dichloromethane and 0.5 L ethyl acetate.
  • the pH of the aqueous phase is brought to pH 9.2 with 260 ml of 6N sodium hydroxide solution.
  • the aqueous phase is separated off and the organic phase is washed three times with 1 l each of normal aqueous sodium bicarbonate solution.
  • the organic phase is over
  • the crude product is dissolved in 1.5 L of ethyl acetate. At a temperature of 50-55 ° C, 2.5 L of methyl tert-butyl ether are added. At 45 ° C is inoculated and stirred with cooling to room temperature for 16 hours. The suspension is stirred for 3.5 hours at 0-5 ° C and the precipitate is filtered off with suction. The filter cake is washed with methyl tert-butyl ether / ethyl acetate (2: 1) and methyl tert-butyl ether. The product is dried in a vacuum oven at 50 ° C. This gives 236 g of crystalline product of the compound of formula (I) as anhydrate Form I.
  • the crude product of the reaction described above can also be crystallized directly as crystalline monohydrate from 1-propanol / demineralized water.
  • the hydrates and anhydrates according to the invention are characterized by DSC / TG (Differential Scanning Calorimetry / Thermogravimetry) and XRD (X-ray powder diffractograms) (Table 1-5, Figures Ia to 5a).
  • the DSC / TG measurements were carried out using devices from Mettler Toledo (DSC 821 and TGA 851). The sample amount was between 2 and 10 mg for DSC measurements and 10 to 30 mg for TG measurements. The heating rates were 10 K / min, the measurements were carried out under inert atmosphere (nitrogen purge).
  • anhydrate I, anhydrate II and monohydrate of the compound of the formula (I) according to the invention can be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active substances.
  • Suitable application forms are, for example, tablets, capsules, suppositories, solutions, in particular solutions for injection (s.c., i.V., i.m.) and infusion, juices, emulsions or dispersible powders.
  • the proportion of the pharmaceutically active compound (s) in each case in the range of 0.01 to 90 wt .-%, preferably 0.1 to 50 wt .-% of the total composition, i. in amounts sufficient to reach the dosage range given below.
  • the said doses may, if necessary, be given several times a day.
  • Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example iner
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers.
  • the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used.
  • Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, for example flavorings, such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example Boehringer Ingelheim - 24 - 1-1758-out
  • Injection and infusion solutions are in the usual way, eg. with the addition of isotonic agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, if appropriate using emulsifiers and / or dispersants, wherein, for example, when using water as a diluent organic solvents may optionally be used as solubilizers or auxiliary solvents , manufactured and filled into injection vials or ampoules or infusion bottles.
  • preservatives such as p-hydroxybenzoates
  • stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid
  • the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
  • suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • water pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), oils of vegetable origin (e.g., peanut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerin), carriers such as e.g.
  • paraffins e.g., petroleum fractions
  • oils of vegetable origin e.g., peanut or sesame oil
  • mono- or polyfunctional alcohols e.g., ethanol or glycerin
  • carriers such as e.g.
  • ground natural minerals eg kaolins, clays, talc, chalk
  • ground synthetic minerals eg fumed silica and silicates
  • sugars eg pipe, milk and dextrose
  • emulsifiers eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone
  • lubricants eg Magnesium stearate, talc, stearic acid and sodium lauryl sulfate.
  • the application is carried out in a customary manner, preferably orally, via injection or transdermally.
  • the tablets may of course also contain additives such as, for example, sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, Boehringer Ingelheim - 25 - 1-1758-out
  • aqueous suspensions the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
  • solutions of the active ingredients may be employed using suitable liquid carrier materials.
  • the dosage for intravenous use is 1 - 1000 mg per hour, preferably between 5 - 500 mg per hour.
  • the finely ground active substance, lactose and part of the corn starch are mixed together.
  • the mixture is sieved, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried.
  • the granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together.
  • the mixture is compressed into tablets of suitable shape and size.
  • the finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remainder of the corn starch and water to a granulate which is dried and sieved.
  • the active ingredient is dissolved in water at its own pH or optionally at pH 3.5-6.5 and treated with sodium chloride as isotonan.
  • the resulting solution is filtered pyrogen-free and the filtrate filled under aseptic conditions in ampoules, which are then sterilized and sealed.
  • the vials contain 5 mg, 25 mg and 50 mg active ingredient.
EP05772062A 2004-08-14 2005-08-11 Hydrate und polymorphe des 4-[[(7r)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl|]amino]-3-methoxy-n-(1-methyl-4-piperidinyl)-benzamid, verfahren zu deren herstellung und deren verwendung als arzneimittel Withdrawn EP1778691A1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05772062A EP1778691A1 (de) 2004-08-14 2005-08-11 Hydrate und polymorphe des 4-[[(7r)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl|]amino]-3-methoxy-n-(1-methyl-4-piperidinyl)-benzamid, verfahren zu deren herstellung und deren verwendung als arzneimittel

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP04019366 2004-08-14
PCT/EP2005/008736 WO2006018222A1 (de) 2004-08-14 2005-08-11 Hydrate und polymorphe des 4-[[(7r)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl]amino]-3-methoxy-n-(1-methyl-4-piperidinyl)-benzamid, verfahren zu deren herstellung und deren verwendung als arzneimittel
EP05772062A EP1778691A1 (de) 2004-08-14 2005-08-11 Hydrate und polymorphe des 4-[[(7r)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl|]amino]-3-methoxy-n-(1-methyl-4-piperidinyl)-benzamid, verfahren zu deren herstellung und deren verwendung als arzneimittel

Publications (1)

Publication Number Publication Date
EP1778691A1 true EP1778691A1 (de) 2007-05-02

Family

ID=35311878

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05772062A Withdrawn EP1778691A1 (de) 2004-08-14 2005-08-11 Hydrate und polymorphe des 4-[[(7r)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl|]amino]-3-methoxy-n-(1-methyl-4-piperidinyl)-benzamid, verfahren zu deren herstellung und deren verwendung als arzneimittel

Country Status (19)

Country Link
US (3) US7728134B2 (ja)
EP (1) EP1778691A1 (ja)
JP (1) JP2008509953A (ja)
KR (1) KR101221864B1 (ja)
CN (1) CN101006090A (ja)
AR (1) AR052404A1 (ja)
AU (1) AU2005274340B2 (ja)
BR (1) BRPI0514351A2 (ja)
CA (1) CA2578098A1 (ja)
EA (1) EA011407B1 (ja)
EC (1) ECSP077249A (ja)
IL (1) IL181302A0 (ja)
MX (1) MX2007001854A (ja)
NO (1) NO20070752L (ja)
NZ (1) NZ553649A (ja)
PE (1) PE20060424A1 (ja)
TW (1) TWI370131B (ja)
UA (1) UA87865C2 (ja)
WO (1) WO2006018222A1 (ja)

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