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WO2005097819A1 - Steroides d-homo-17-chloro-16(17)-ene - Google Patents

Steroides d-homo-17-chloro-16(17)-ene Download PDF

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Publication number
WO2005097819A1
WO2005097819A1 PCT/EP2005/003792 EP2005003792W WO2005097819A1 WO 2005097819 A1 WO2005097819 A1 WO 2005097819A1 EP 2005003792 W EP2005003792 W EP 2005003792W WO 2005097819 A1 WO2005097819 A1 WO 2005097819A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydroxy
chloro
dien
homo
group
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/EP2005/003792
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German (de)
English (en)
Inventor
Sven Ring
Ralf Wyrwa
Günter Kaufmann
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.)
Bayer Pharma AG
Original Assignee
Schering AG
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 Schering AG filed Critical Schering AG
Priority to EP05739526A priority Critical patent/EP1735331A1/fr
Priority to AU2005231970A priority patent/AU2005231970A1/en
Priority to EA200601842A priority patent/EA200601842A1/ru
Priority to MXPA06012849A priority patent/MXPA06012849A/es
Priority to CA002563541A priority patent/CA2563541A1/fr
Publication of WO2005097819A1 publication Critical patent/WO2005097819A1/fr
Anticipated expiration legal-status Critical
Priority to NO20065126A priority patent/NO20065126L/no
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens

Definitions

  • the invention relates to D-homo-17-chloro-16 (17) -en steroids of the general formula I.
  • WO 99/46279 discloses D-homo-16-chloro-17-oxosteroids which inhibit the 17 ⁇ -hydroxysteroid dehydrogenase.
  • DE 19712488 discloses sulfamates of D-homostratrienes which, however, are unsubstituted on the 17a carbon.
  • D-homo-17a-chloro-16 (17) -en steroids show antiandrogenic activity (EP 52799).
  • D-Homo ⁇ 17a-substituted-Pregnane- and androstanes, in which the 16 (17) double bond is absent, are known from DE 2700267. Such compounds have an anesthetic effect.
  • D-homo-11 ⁇ -aryl-17-chloro-16 (17) -en steroids are known from the prior art which are strong antigestagens (DE 4042005, Steroids, 1994, 59, 176-80). Also known is 17ass-hydroxy-7 ⁇ -methyl-D-homoestra-4,16-dien-3-one, which has androgenic and antigonadotropic properties (Steroids, 1990, 55, 59-64).
  • D-homo-17-chloro-16 (17) -en steroids of the androstane, 19-norandrostane and 13-ethylgonane series are not yet known.
  • the object of the present invention is therefore to provide new compounds with androgenic activity.
  • R 1 for a C 6 alkyl group
  • R 2 for a hydroxy group, C- ⁇ - 10 alkyloxy-, C ⁇ - 15 -acyloxy-, C 6 - ⁇ 5 -cycloalkylacyloxy-, C 7 -i 5 -arylacyloxy-, C 7 . 15 arylalkyloxy or a C 7 .
  • R 3 for a hydroxyl group, C 10 alkyloxy, C 1 5 acyloxy, C 6 5 cycloalkylacyloxy, C. 15 aryl acyloxy, C 7 . 15 arylalkyloxy or a C 7 - ⁇ 5 alkylaryloxy group,
  • R 2 and R 3 together represent a keto, methylene, difluoromethylene group or form a spirooxirane or a 2,2-dimethyl-1,3-dioxolane, including the 17a-C atom,
  • STEROID stands for a steroidal partial ring system of the formulas A, B, C, D E and F, which are listed below,
  • R 6 represents a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group or a trifluoromethyl group
  • X and Z each represent a hydrogen atom or together an oxygen atom or a hydroxyimino group
  • R 7 is a hydrogen atom, a d- 6 alkyl group or a C- ⁇ - 6 alkenyl group
  • R 8 is a hydrogen atom, a halogen atom, together with R 9 is a double bond
  • R 9 represents a hydrogen atom, a hydroxyl group, a halogen atom, a methyl or ethyl group or together with R 8 a double bond,
  • R 10 represents a hydrogen atom, a methyl group, a nitrile group, a hydroxymethylene or formyl group,
  • R 11 represents a hydrogen atom, a methyl group, a nitrile group
  • R 10 and R 11 in addition to the meanings given above, together form a double bond or a methylene bridge
  • R 12 is a hydrogen atom or together with R 6 a double bond
  • R 13 and R 14 together represent a double bond, an oxirane ring, a thiirane ring, a [2,3c] oxadiazole, a [3,2c] isoxazole or a [3,2c] pyrazole ring, and Y is an oxygen or nitrogen atom .
  • the meandering lines on R 6 , R 7 , R 8 , R 11 , R 12 , R 13 , R 14 mean that these substituents can be ⁇ - or ⁇ -permanent.
  • the compounds according to the invention have androgenic activity.
  • the C 6 alkyl group is a branched or unbranched alkyl radical which, for example, by a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or tert-butyl group, n- Pentyl, i-pentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl group is formed.
  • halogen atom stands for a fluorine, chlorine, bromine or iodine atom.
  • R 1 preferably denotes a methyl group or an ethyl group, the methyl group being particularly preferred.
  • R 2 preferably denotes a hydroxyl or esterified hydroxyl group, in particular a formyloxy group, acetyloxy group, propanoyloxy group, butyryloxy group, [(trans-4-butylcyclohexyl) carbony] oxy group, phenylpropanoyloxy group, iso-butyryloxy group or undecanoyloxy group.
  • R 3 preferably denotes a hydrogen atom, a methyl, ethyl, ethynyl, hydroxymethyl, chloromethyl, bromomethyl, cyanomethyl, azidomethyl, rhodanomethyl, methoxymethyl group.
  • R 6 preferably denotes a hydrogen atom, an F, Cl, Br atom, a hydroxyl group, a methyl group or a trifluoromethyl group, X and Z preferably together represent an oxygen atom,
  • R 7 preferably denotes a hydrogen atom or a methyl group
  • R 8 preferably denotes a hydrogen atom or a fluorine atom
  • R 9 preferably denotes a hydrogen atom, a hydroxyl, a methyl group, a fluorine or chlorine atom
  • R 10 preferably denotes a hydrogen atom, a methyl, formyl or a nitrile group
  • R 11 preferably denotes a hydrogen atom or a methyl group
  • R 12 preferably represents a hydrogen atom, a hydroxymethyl or formyl group
  • R 13 and R 14 preferably together represent a thiirane ring, a [2,3c] oxadiazole, a [3,2c] isooxazal ring or a [3,2c ] Pyrazole ring
  • Y preferably represents an oxygen atom.
  • STEROID stands for a steroidal ring system of sub-formula A, preferably means
  • R 1 is a methyl group
  • R 6 is a fluorine, chlorine, bromine atom, a trifluoromethyl or a hydroxy group
  • R 7 is a methyl group
  • R 8 is a fluorine atom and / or
  • R 9 is a hydroxy group.
  • STEROID stands for a steroidal ring system of sub-formula B, preferably means
  • R 1 is a methyl group
  • R 6 is a fluorine, chlorine, bromine atom, a trifluoromethyl or a hydroxy group
  • R 7 is a methyl group and / or
  • R 9 is a hydroxy group.
  • STEROID stands for a ring system of sub-formula C, preferably means
  • R 6 is a fluorine, chlorine, bromine atom, a trifluoromethyl or a hydroxy group
  • R 7 is a methyl group
  • R 9 is a hydroxy group and / or
  • R 12 is a hydroxymethyl or formyl group.
  • STEROID stands for a ring system of sub-formula D, means
  • R 1 is a methyl group
  • R 6 is a fluorine, chlorine, bromine atom, a trifluoromethyl or a hydroxy group
  • R 7 is a methyl group and / or
  • Y is an oxygen atom
  • STEROID stands for a ring system of sub-formula E, preferably means
  • R 1 is a methyl group and / or
  • R 9 is a hydroxy group. Particularly preferred compounds are listed below:
  • the compounds according to the invention have androgenic activity in vitro and also in vivo (Hershberger test on rats).
  • the receptor binding affinities on the androgen receptor listed below illustrate the in vitro activity.
  • the receptor binding affinity was determined by competitive binding of a specifically binding 3H-labeled hormone (tracer) and the compound to be tested
  • Receptors in the cytosol from animal target organs Receptor saturation and
  • the D-homo-17-chloro-16 (17) -en steroids according to the invention advantageously have a very high binding affinity for the androgen receptor.
  • the present invention therefore also relates to pharmaceutical compositions which contain at least one D-homo-17-chloro-16 (17) -en steroid of the general formula (I) or its salt, optionally together with pharmaceutically acceptable auxiliaries and carriers.
  • These pharmaceutical compositions and medicaments can be intended for oral, rectal, vaginal, subcutaneous, percutaneous, transdermal, buccal, intravenous or intramuscular application.
  • conventional carriers and / or diluents they contain at least one compound of the general formula I or its salt.
  • the pharmaceuticals according to the present invention are produced in a known manner with the usual solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries according to the desired type of application with a suitable dosage.
  • the preferred preparations are in a dosage form which is suitable for oral administration. Dosage forms of this type are, for example, tablets, film-coated tablets, coated tablets, capsules, pills, plasters, powders, solutions or suspensions or even depot forms.
  • parenteral preparations such as injection solutions are also suitable.
  • Suppositories and agents for vaginal use may also be mentioned as preparations.
  • Corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents for achieving one Depot effects such as carboxylpolymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained.
  • the tablets can also consist of several layers.
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
  • the coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Solutions or suspensions with the compounds of general formula I according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and z.
  • B. contain flavorings such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates.
  • Capsules containing the compounds of general formula I can be prepared, for example, by mixing the compound (s) of general formula I with an inert carrier such as milk sugar or sorbitol and encapsulating them in gelatin capsules.
  • Suitable suppositories can be produced, for example, by mixing them with suitable carriers such as neutral fats or polyethylene glycol or their derivatives.
  • Known basic steroid bodies can be used to prepare the compounds of the general formula I with the partial structures A-F.
  • the following steroid bodies can be used, for example:
  • dichlorocarbene can be obtained from chloroform by treatment with bases such as, for example, potassium hydroxide or from the sodium salt of trichloroacetic acid by heating in a suitable solvent, such as, for example, Tetrachlorethylene or chloroform, advantageously with the addition of a phase transfer catalyst.
  • bases such as, for example, potassium hydroxide or from the sodium salt of trichloroacetic acid by heating in a suitable solvent, such as, for example, Tetrachlorethylene or chloroform, advantageously with the addition of a phase transfer catalyst.
  • a suitable solvent such as, for example, Tetrachlorethylene or chloroform
  • inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid
  • organic acids include acetic acid, propionic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, ascorbic acid, oxalic acid, Salicylic acid, tartaric acid, citric acid, lactic acid, malic acid, mandelic acid, cinnamic acid and methanesulfonic acid.
  • 6-methoxy-3,5-cycIo-17 - [(trimethylsilyl) oxy] -androstan-16-ene is refluxed in 400 ml of chloroform with 141 g of trichloroacetic acid sodium salt and 3.3 g of benzyltriethylammonium chloride for 2 hours. It is poured into 1 l of saturated sodium bicarbonate solution, worked up extractively with chloroform and the residue is chromatographed on silica gel for purification. 17-Chloro-6-methoxy-3,5-cyclo-17a-homo-androstan-16-ene-17a-one is obtained.
  • 17ass acetoxy-17-chloro-6-methoxy-3,5-cyclo-17a-homoandrostan-16-ene are refluxed in 200 ml of acetone, 21 ml of water and 6 ml of 60% perchloric acid for 1 hour. Then it is neutralized with 10% sodium hydrogen carbonate solution and concentrated. The residue is worked up extractively with ethyl acetate. After concentrating the organic extract, 17ass-acetoxy-17-chloro-17a-homoandrost-5,16-dien-3ß-ol is obtained, which is processed directly.
  • methyl magnesium iodide prepared from 2.5 g of magnesium and 6.4 ml of methyl iodide in 80 ml of diethyl ether
  • the mixture is cooled to -5 ° C. and 1 g of copper acetate monohydrate (dissolved in 50 ml of THF ) too. It is cooled to -20 ° C. and then a solution of 5 g of 17-chloro-17ass-hydroxy-17a-homoandrost ⁇ 4,6,16 ⁇ trien-3 ⁇ one in 80 ml THF is added dropwise.
  • 17-chloro-17ass-hydroxy-17a-homo-estra-4,6,16-trien-3-one can easily be made from 17-chloro-17ass-hydroxy-17a ⁇ homo-estra-4,16-diene-3- on by the method of JA Campbell et al (Steroids 1963, 317). Stage 2 17-chloro-17ass-hydroxy-7 ⁇ -methyl-17a-homo-estra-4, 16-dien-3-one:
  • methyl magnesium iodide prepared from 2.5 g of magnesium and 6.4 ml of methyl iodide in 80 ml of diethyl ether
  • the mixture is cooled to -5 ° C. and 1 g of copper acetate monohydrate (dissolved in 50 ml of THF ) too. It is cooled to -20 ° C. and then a solution of 5 g of 17-chloro-17ass-hydroxy-17a-homo-estr-4,6,16-trien-3-one in 80 ml of THF is added dropwise. After 2 hours, pour on ice water / 2N sulfuric acid and extract with 3 times 80 ml of ethyl acetate.
  • 17-Di - (trimethylsilyloxy) -5 ⁇ -H-androst-16-ene is refluxed in 400 ml of chloroform with 47 g of tnchloroacetic acid sodium salt and 1.1 g of benzyltriethylammonium chloride for 2 hours. It is poured into 300 ml of saturated sodium bicarbonate solution, worked up extractively with chloroform and the residue is chromatographed on silica gel for purification. 17-Chloro-3 ⁇ -trimethylsilyloxy -17a-homo-5 ⁇ -H-androst-16-en-17-one is obtained.
  • the 17-chloro-3ß-acetoxy-17a-homo-5-H-androst-16-en-17ass-ol (5 g) obtained is treated with 3,4-dihydro-2H-pyran in the presence of pyridinium tosylate in 100 ml of dichloromethane transferred to the 17a-tetrahydropyranyl ether and the acetate in the 3ß position is saponified with 5 g of potassium hydroxide in 100 ml of boiling methanol.

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

Abstract

L'invention concerne des stéroïdes D-homo-17-chloro-16(17)-ène de formule (I) présentant une activité androgène. L'invention concerne également des procédés permettant de les produire et des compositions pharmaceutiques qui contiennent lesdits composés, ainsi que leur utilisation pour produire des médicaments.
PCT/EP2005/003792 2004-04-08 2005-04-07 Steroides d-homo-17-chloro-16(17)-ene Ceased WO2005097819A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP05739526A EP1735331A1 (fr) 2004-04-08 2005-04-07 Steroides d-homo-17-chloro-16(17)-ene
AU2005231970A AU2005231970A1 (en) 2004-04-08 2005-04-07 D-homo-17-chloro-16(17)en steroids
EA200601842A EA200601842A1 (ru) 2004-04-08 2005-04-07 D-гомо-17-хлор-16(17)-ен-стероиды
MXPA06012849A MXPA06012849A (es) 2004-04-08 2005-04-07 D-homo-17-cloro-16(17)eno esteroides.
CA002563541A CA2563541A1 (fr) 2004-04-08 2005-04-07 Steroides d-homo-17-chloro-16(17)-ene
NO20065126A NO20065126L (no) 2004-04-08 2006-11-07 D-homo-17-klor-16(17)-en-steroider.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004018441A DE102004018441B4 (de) 2004-04-08 2004-04-08 D-Homo-17-chlor-16(17)en Steroide
DE102004018441.0 2004-04-08

Publications (1)

Publication Number Publication Date
WO2005097819A1 true WO2005097819A1 (fr) 2005-10-20

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PCT/EP2005/003792 Ceased WO2005097819A1 (fr) 2004-04-08 2005-04-07 Steroides d-homo-17-chloro-16(17)-ene

Country Status (18)

Country Link
EP (1) EP1735331A1 (fr)
KR (1) KR20070007910A (fr)
CN (1) CN1997659A (fr)
AR (1) AR048536A1 (fr)
AU (1) AU2005231970A1 (fr)
CA (1) CA2563541A1 (fr)
CR (1) CR8736A (fr)
DE (1) DE102004018441B4 (fr)
EA (1) EA200601842A1 (fr)
EC (1) ECSP066973A (fr)
GT (1) GT200500084A (fr)
MX (1) MXPA06012849A (fr)
NO (1) NO20065126L (fr)
PA (1) PA8629401A1 (fr)
SV (1) SV2005002076A (fr)
TW (1) TW200603812A (fr)
WO (1) WO2005097819A1 (fr)
ZA (1) ZA200609275B (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4788218A (en) * 1984-05-21 1988-11-29 Sri International 17 a β-hydroxy-7 α-methyl-d-homo-19-norandrost-4,16-diene-3-one and the 17-esters thereof: methods of preparation and uses
WO1992011279A1 (fr) * 1990-12-22 1992-07-09 Schering Aktiengesellschaft Berlin Und Bergkamen D-HOMO-(16-EN)-11β-ARYL-4-×STRENES, LEUR PROCEDE DE PRODUCTION ET LEUR UTILISATION COMME MEDICAMENTS
CN1074910C (zh) * 1993-08-21 2001-11-21 雀巢制品公司 一种调味品的生产方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10151365A1 (de) * 2001-10-17 2003-04-30 Schering Ag 17-Chlor-D-Homosteroide als selektive Estrogenrezeptorantagonisten

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4788218A (en) * 1984-05-21 1988-11-29 Sri International 17 a β-hydroxy-7 α-methyl-d-homo-19-norandrost-4,16-diene-3-one and the 17-esters thereof: methods of preparation and uses
WO1992011279A1 (fr) * 1990-12-22 1992-07-09 Schering Aktiengesellschaft Berlin Und Bergkamen D-HOMO-(16-EN)-11β-ARYL-4-×STRENES, LEUR PROCEDE DE PRODUCTION ET LEUR UTILISATION COMME MEDICAMENTS
CN1074910C (zh) * 1993-08-21 2001-11-21 雀巢制品公司 一种调味品的生产方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AVERY M A ET AL: "Synthesis and testing of 17a.beta.-hydroxy-7.alpha.-methyl-D-homoestr a-4,16-dien-3-one: a highly potent orally active androgen", STEROIDS: STRUCTURE, FUNCTION, AND REGULATION, ELSEVIER SCIENCE PUBLISHERS, NEW YORK, NY, US, vol. 55, no. 2, February 1990 (1990-02-01), pages 59 - 64, XP002118688, ISSN: 0039-128X *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; "Preparation of 11.beta.-aryl-D-homoestra-4,16-dienes as contraceptives", XP002341061, retrieved from STN Database accession no. 1994:323998 *
DATABASE EPODOC EUROPEAN PATENT OFFICE, THE HAGUE, NL; XP002341062 *

Also Published As

Publication number Publication date
CR8736A (es) 2007-08-28
ZA200609275B (en) 2009-08-26
EA200601842A1 (ru) 2007-04-27
EP1735331A1 (fr) 2006-12-27
NO20065126L (no) 2007-01-04
GT200500084A (es) 2006-03-24
AR048536A1 (es) 2006-05-03
MXPA06012849A (es) 2007-01-26
TW200603812A (en) 2006-02-01
PA8629401A1 (es) 2006-07-03
AU2005231970A1 (en) 2005-10-20
DE102004018441A1 (de) 2005-11-03
CN1997659A (zh) 2007-07-11
SV2005002076A (es) 2005-12-06
ECSP066973A (es) 2006-12-29
DE102004018441B4 (de) 2007-12-20
KR20070007910A (ko) 2007-01-16
CA2563541A1 (fr) 2005-10-20

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