EP1638553A1 - Nouvelle utilisation i - Google Patents

Nouvelle utilisation i

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Publication number
EP1638553A1
EP1638553A1 EP04749034A EP04749034A EP1638553A1 EP 1638553 A1 EP1638553 A1 EP 1638553A1 EP 04749034 A EP04749034 A EP 04749034A EP 04749034 A EP04749034 A EP 04749034A EP 1638553 A1 EP1638553 A1 EP 1638553A1
Authority
EP
European Patent Office
Prior art keywords
thiazol
ethyl
amino
sulfonyl
chloro
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Withdrawn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
EP04749034A
Other languages
German (de)
English (en)
Inventor
Cecilia Nilsson
Catrine Dreifeldt
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.)
Swedish Orphan Biovitrum AB
Original Assignee
Biovitrum AB
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 Biovitrum AB filed Critical Biovitrum AB
Publication of EP1638553A1 publication Critical patent/EP1638553A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the use of chemical compounds for wound healing, said compounds acting on the human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme (ll ⁇ HSDl).
  • Cortisol performs a broad range of metabolic functions and other functions.
  • the multitude of glucocorticoid action is exemplified in patients with prolonged increase in plasma glucocorticoids, so called "Cushing's syndrome".
  • Patients with Cushing's syndrome have prolonged increase in plasma glucocorticoids and exhibit impaired glucose tolerance, type 2 diabetes, central obesity, and osteoporosis. These patients also have impaired wound healing and brittle skin (1).
  • Glucocorticoids have been shown to increase risk of infection and delay healing of open wounds (2). Patients treated with glucocorticoids have 2-5-fold increased risk of complications when undergoing surgery (3).
  • EP 0902288 discloses a method for diagnosing the status of wound healing in a patient, comprising detecting cortisol levels in said wound.
  • the authors suggest that elevated levels of cortisol in wound fluid, relative to normal plasma levels in healthy individuals, correlates with large, non-healing wounds (4).
  • 1 l ⁇ -HSD catalyzes the conversion of cortisol to cortisone, and vice versa.
  • the parallel function of 1 l ⁇ -HSD in rodents is the interconversion of corticosterone and 11-dehydrocorticosterone (5).
  • Two isoenzymes of 11 ⁇ -HSD, 1 l ⁇ - HSD 1 and 1 l ⁇ -HSD2 have been characterized, and differ from each other in function and tissue distribution (6).
  • 1 l ⁇ -HSD 1 is expressed in numerous tissues like liver, adipose tissue, adrenal cortex, gonads, lung, pituitary, brain, eye etc (7-9).
  • the function of 11 ⁇ -HSD 1 is to fine-tune local glucocorticoid action.
  • 11 ⁇ -HSD activity has been shown in the skin of humans and rodents, in human fibroblasts and in rat skin pouch tissue (10-13).
  • Wound healing consists of serial events including inflammation, fibroblast proliferation, secretion of ground substances, collagen production, angio genesis, wound contraction and epithelialization. It can be divided in three phases; inflammatory, proliferative and remodeling phase (reviewed in (2)).
  • glucocorticoids In surgical patients, treatment with glucocorticoids increases risk of wound infection and delay healing of open wounds. It has been shown in animal models that restraint stress slows down cutaneous wound healing and increases susceptibility to bacterial infection during wound healing. These effects were reversed by treatment with the glucocorticoid receptor antagonist RU486 (14, 15). Glucocorticoids produce these effects by suppressing inflammation, decrease wound strength, inhibit wound contracture and delay epithelialization (2). Glucocorticoids influence wound healing by interfering with production or action of cytokines and growth factors like IGF, TGF- ⁇ , EGF, KGF and PDGF (16-19). It has also been shown that glucocorticoids decrease collagen synthesis in rat and mouse skin in vivo and in rat and human fibroblasts (20).
  • WO 01/90090 discloses compounds of the formula (I) as defined hereinafter, which compounds inhibit the human 1 l ⁇ -HSDl, and may be useful for treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders and immune disorders.
  • Other 1 l ⁇ -HSDl inhibitors are disclosed in e.g. WO 01/90091; WO 01/90092; WO 01/90093; WO 01/90094; WO 03/044000; WO 03/044009; WO 03/043999; and Swedish patent application No. SE 0301504-7, filed on May 21, 2003.
  • WO 02/072084 relates to glycyrrhetinic acid derivatives, progesterone and progesterone derivatives as 1 l ⁇ -HSDl inhibitors for wound healing.
  • 1 l ⁇ -HSDl inhibitors according to the present invention for wound healing has not previously been disclosed.
  • this invention provides a method for promoting wound healing, said method comprising administering to a mammal, including man, in need of wound healing an effective amount of an inhibitor of 1 l ⁇ -hydroxysteroid dehydrogenase type 1, wherein the inhibitor of 1 l ⁇ - hydroxysteroid dehydrogenase type 1 is a compound of the formula (I):
  • T is an aryl ring or heteroaryl ring or aryl-C -alkenyl ring, optionally independently substituted by [R] n , wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C ⁇ - 6 -alkyl, optionally halogenated C ⁇ - 6 -alkoxy, C ⁇ - 6 -alkylsulfonyl, carboxy, cyano, nitro, halogen, amine which is optionally mono- or di-substituted, amide which is optionally mono- or di-substituted, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings can further be optionally substituted in one or more positions independently of each other by C ⁇ - 6 -acyl, C ⁇ - 6 -alkylthio, cyano,
  • R 1 is hydrogen or C ⁇ - 6 -alkyl
  • X is CH 2 or CO;
  • Y is CH 2 , CO or a single bond;
  • B is hydrogen or C ⁇ - 6 -alkyl
  • R 2 is selected from C ⁇ - 6 -alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4- mo holinolinylmethylene, C ⁇ - 6 -alkoxycarbonyl, and 5-methyl-l,3,4-oxadiazol-2-yl; NR 3 R 4 , wherein R 3 and R 4 are each independently selected from hydrogen, C ⁇ - 6 -alkyl, optionally halogenated C ⁇ - 6 -alkylsulfonyl, C ⁇ - 6 -alkoxy, 2-methoxyethyl, 2-hydroxyethyl, 1-methylimidazolylsulfonyl, Ci- ⁇ -acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl,
  • R 3 and R 4 are each independently selected from hydrogen, C ⁇ - 6 - alkyl or form together morpholinyl; R 5 O, wherein R 5 is hydrogen, optionally halogenated C ⁇ - 6 -alkyl, aryl, heteroaryl, C ⁇ - 6 - acyl, C ⁇ - 6 -alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; and pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.
  • T is selected from 5 -chloro- 1,3 -dimethyl- lH-pyrazol-4-yl; 4-chloro-2,3,l- benzoxadiazolyl; 5-(dimethylamino)-l-naphthyl; l-methylimidazol-4-yl; 1-naphthyl; 2- naphthyl; (E)-2-phenylethenyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3- isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1 -methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetylphenyl, benzene
  • R 1 is hydrogen or methyl
  • X is CH 2 or CO
  • Y is CH 2 , CO or a single bond
  • B is hydrogen or methyl
  • R 2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl;
  • R 3 and R 4 are each independently selected from acetyl, 1,3- benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexylmethyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(lH-indol-3- yl)ethyl, isopropyl, methoxy, 2-methoxyethyl, methyl, 4-(l-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, propyl, trifluoromethylsulfonyl; or
  • NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2-(3,4- dihydro-2(lH)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl-l- piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4- methyl-2-oxopiperazinyl, 4-methylpiperazinyl, mo ⁇ holinyl, (lS,4S)-2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomo ⁇ holinyl, 3-oxo-l,4-oxazepinyl, 2- oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl;
  • R 3 and R 4 are each independently selected from ethyl, hydrogen or form together mo ⁇ holinyl;
  • R 5 is selected from acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2- furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, propionyl, 3-pyridinyl, and 2,2,2-trifluoroethyl.
  • the said method is a method for the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing.
  • medical conditions are diabetes, and conditions caused by treatment with steroids, in particular glucocorticoids.
  • the method according to the invention is also intended for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
  • the compounds referred to above may also be used in the manufacture of a medicament for promoting wound healing, e.g. for the treatment or prophylaxis of a medical condition involving delayed or impaired wound healing.
  • a medical condition involving delayed or impaired wound healing.
  • medical conditions are diabetes, and conditions caused by treatment with steroids, in particular glucocorticoids.
  • the compounds referred to above may also be used for the promotion of wound healing in chronic wounds, such as diabetic ulcers, venous ulcers or pressure ulcers.
  • aryl in the present description is intended to include aromatic rings
  • phenyl (Ph) and naphthyl which optionally may be substituted by C ⁇ - 6 -alkyl.
  • substituted aryl groups are benzyl and 2-methylphenyl.
  • heteroaryl means in the present description a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium.
  • heteroaryl rings examples include pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiazole, 2,1,3- benzoselenadiazole, benzimidazole, indazole, benzodioxane, indan
  • Examples of monocyclic heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, and tetrazole.
  • heterocyclic in the present description is intended to include unsaturated as well as partially and fully saturated mono-, bi- and tricyclic rings having from 4 to 14, preferably 4 to 10 ring atoms, such as, for example, the heteroaryl groups mentioned above as well as the corresponding partially saturated or fully saturated heterocyclic rings.
  • exemplary saturated heterocyclic rings are azetidine, pyrrolidine, piperidine, piperazine, mo ⁇ holine, thiomo ⁇ holine and 1,4-oxazepane.
  • C ⁇ _6-alkyl in the compound of formula (I) according to the present application is preferably C ⁇ _4-alkyl.
  • Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.
  • C ⁇ _ 6 -alkyl all subgroups thereof are contemplated such as C ⁇ - 5 -alkyl, C ⁇ - 4 -alkyl, C 2 . 6 -alkyl, C 2 - 5 -alkyl, C 2 . 4 -alkyl, C . 3 -alkyl, C 3 . 6 -alkyl, C 4 . 5 -al yl, etc.
  • C ⁇ _6-alkoxy in the compound of formula (I) according to the present application may be straight or branched, is preferably C _4-alkoxy.
  • Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy.
  • C ⁇ - 6 -alkoxy all subgroups thereof are contemplated such as C ⁇ - 5 -alkoxy, C ⁇ - 4 -alkoxy, C 2 . 6 -alkoxy, C 2 - 5 - alkoxy, C 2 .
  • C ⁇ _6-acyl in the compound of formula (I) according to the present application may be saturated or unsaturated and is preferably C ⁇ _4-acyl.
  • exemplary acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, butenoyl (e.g. 3- butenoyl), hexenoyl (e.g. 5-hexenoyl).
  • C ⁇ - 6 -acyl For parts of the range "C ⁇ - 6 -acyl" all subgroups thereof are contemplated such as C ⁇ - 5 -acyl, C ⁇ - 4 -acyl, C 2 - 6 -acyl, C 2 - 5 -acyl, C 2 . -acyl, C 2 - 3 -acyl, C 3 . 6 -acyl, C 4 . 5 -acyl, etc.
  • C 2 - 6 -alkenyl in the compound of formula (I) according to the present application is preferably C 2 - 4 -alkenyl.
  • Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1- pentenyl, 2-pentenyl, 1-hexenyl, and 2-hexenyl.
  • C 2 . 6 -alkenyl all subgroups thereof are contemplated such as C 2 - 5 -alkenyl, C 2 - 4 -alkenyl, C 2 . 3 -alkenyl, C 3 . 6 -alkenyl, C 4 . 5 -alkenyl, etc.
  • halogen in the present description is intended to include fluorine, chlorine, bromine and iodine.
  • sulfanyl in the present description means a thio group.
  • mono- or di-substituted is meant in the present description that the functionalities in question may be substituted with independently H, C ⁇ - 6 -acyl, C ⁇ _ 6 - alkenyl, C ⁇ - 6 -(cyclo)alkyl, aryl, pyridylmethyl, or heterocyclic rings e.g. azetidine, pyrrolidine, piperidine, piperazine, mo ⁇ holine and thiomo ⁇ holine, which heterocyclic rings optionally may be substituted with C ⁇ - 6 -alkyl.
  • optionally mono- or disubstituted is meant in the present description that the functionalities in question may also be substituted with independently hydrogen.
  • stable referes to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the pu ⁇ oses detailed herein (e.g., therapeutic administration to a subject for the treatment of disease, 11- ⁇ -HSDl inhibition, 11 - ⁇ -HSD 1 -mediated disease).
  • prodrug forms in the present description means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug (see Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8 th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs, p. 13-15).
  • “Pharmaceutically acceptable” means in the present description being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” mean in the present description salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
  • Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
  • Base addition salts may be formed with organic and inorganic bases, such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline and the like.
  • the compounds of formula (I) can be prepared according to the methods described in WO 01/90090.
  • the compounds of formula (I) can preferably be topically administered.
  • the compounds could also be administered by other routes, for instance orally, intraperitoneally, intraarticularly, intracranially, intradermally, intramuscularly, intraocularly, intrathecally, intravenously, subcutaneously.
  • Diabetic KKAy mice underwent surgery during anesthesia whereby a catheter was inserted in the jugularis vein. Oral treatment twice daily (200 mg/kg/day) with the 1 l ⁇ - HSDl inhibitor BVT.2733 (3-Chloro-2-methyl-N- ⁇ 4-[2-oxo-2-(l-piperazinyl)ethyl]- l,3-thiazol-2-yl ⁇ benzenesulfonamide; the trifluoroacetate of this compound is disclosed as Example 172A in WO 01/90090), or vehicle started 4-6 days later and continued for 3.5 days.
  • Hutchinson TC Swaniker HP. Wound diagnosis by quantitating cortisol in wound fluids.
  • Beer HD Fassler R, Werner S. Glucocorticoid-regulated gene expression during cutaneous wound repair. Vitam Horm 2000;59:217-39.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

L'invention porte sur un procédé favorisant la cicatrisation des blessures consistant à administrer à un mammifère, homme compris le nécessitant une dose efficace d'un inhibiteur de la 11-b-hydroxystéroid déshydrogénase de type 1, de formule (I) dans laquelle: T, B, X, Y, R1 et R2 sont définis dans la spécification. Ces composés peuvent également utilisés dans la préparation de médicaments favorisant la cicatrisation des blessures.
EP04749034A 2003-06-25 2004-06-21 Nouvelle utilisation i Withdrawn EP1638553A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0301882A SE0301882D0 (sv) 2003-06-25 2003-06-25 New use I
PCT/SE2004/000996 WO2004112784A1 (fr) 2003-06-25 2004-06-21 Nouvelle utilisation i

Publications (1)

Publication Number Publication Date
EP1638553A1 true EP1638553A1 (fr) 2006-03-29

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP04749034A Withdrawn EP1638553A1 (fr) 2003-06-25 2004-06-21 Nouvelle utilisation i

Country Status (9)

Country Link
EP (1) EP1638553A1 (fr)
JP (1) JP2007521264A (fr)
KR (1) KR20060023570A (fr)
CN (1) CN1812784A (fr)
AU (1) AU2004249099A1 (fr)
CA (1) CA2529406A1 (fr)
NO (1) NO20060416L (fr)
SE (1) SE0301882D0 (fr)
WO (1) WO2004112784A1 (fr)

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AU2004249099A1 (en) 2004-12-29
CA2529406A1 (fr) 2004-12-29
WO2004112784A1 (fr) 2004-12-29
KR20060023570A (ko) 2006-03-14
JP2007521264A (ja) 2007-08-02
NO20060416L (no) 2006-03-24
CN1812784A (zh) 2006-08-02
SE0301882D0 (sv) 2003-06-25

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