EP1305289A2 - Neue heteroaryl-derivate und deren verwendung als antitumormittel - Google Patents

Neue heteroaryl-derivate und deren verwendung als antitumormittel

Info

Publication number
EP1305289A2
EP1305289A2 EP01960509A EP01960509A EP1305289A2 EP 1305289 A2 EP1305289 A2 EP 1305289A2 EP 01960509 A EP01960509 A EP 01960509A EP 01960509 A EP01960509 A EP 01960509A EP 1305289 A2 EP1305289 A2 EP 1305289A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
radical
substituted
mono
alkylamino
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Withdrawn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
EP01960509A
Other languages
German (de)
English (en)
French (fr)
Inventor
Peter Emig
Eckhard Günther
Jürgen Schmidt
Bernhard Kutscher
Bernd Nickel
Anita Storch
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.)
Aeterna Zentaris GmbH
Original Assignee
Zentaris 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 Zentaris AG filed Critical Zentaris AG
Publication of EP1305289A2 publication Critical patent/EP1305289A2/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to new heteroaryl derivatives of the general formula 1, their production and use as medicaments, in particular for the treatment of tumors.
  • new pyridine derivatives according to general formula 1
  • R, Ri, R2, 3 can optionally be bonded to the pyridine carbon atoms C 2 to C 6 , are the same or different and, independently of one another, hydrogen, straight-chain or branched (C ⁇ -C ⁇ ) alkyl, (C3-C7) - cycloalkyl, straight-chain or branched (-C-C8) alkylcarbonyl, preferably acetyl, straight-chain or branched
  • Halogen aryl- (-C-Cs) -alkoxy, preferably benzyloxy or phenyl-ethyloxy, nitro, amino, mono- (CrC 4 ) -alkylamino, di- (-C-C 4 ) -alkylamino, (C ⁇ -C ⁇ ) -alkoxycarbonyl -amino, (Ci-CeJ-alkoxycarbonylamino ⁇ CrC ⁇ ) - alkyl, cyano, straight-chain or branched cyano- (-C-C-6) alkyl, Carboxy, (Ci-CsJ-alkoxycarbonyl, substituted with one or more fluorine atoms (-CC 4 ) -alkyl, preferably the trifluoromethyl group, carboxy- (-C- 8 ) -alkyl or (C C8) -alkoxycarbonyl- (-C-C 6 ) alkyl, (C 2 -C 6
  • P, Q independently of one another represent oxygen or in each case two hydrogen atoms (ie -CH 2 -);
  • X is nitrogen or CR 5 , where R 5 is hydrogen or (-CC 6 ) alkyl
  • R 4 is a straight-chain or branched (-CC 2 o) -alkyl radical which can be saturated or unsaturated with one to three double and / or triple bonds and which is unsubstituted or optionally on the same or different C atoms, two or more aryl, heteroaryl,
  • Alkoxycarbonyl with one or more fluorine atoms substituted straight-chain or branched (C ⁇ -C6) -alkyl, preferably trifluoromethyl, hydroxy, straight-chain or branched (C ⁇ -C ⁇ ) -alkoxy, preferably methoxy or ethoxy, with adjacent oxygen atoms also being substituted by (C 1 - C2) - alkylene groups, preferably a methylene group, can be linked,
  • the compounds of the general formula (1) according to the invention which have one or more chiral centers and which occur as racemates can be separated into their optical isomers, ie enantiomers or diastereomers, by methods known per se.
  • the separation can be carried out by column separation on chiral phases or by recrystallization from an optically active solvent or using an optically active acid or base or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, and subsequent elimination of the rest.
  • pyridine derivatives according to the invention of the general formula (1) can be converted into their salts with inorganic or organic acids, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • acids for this are hydrochloric acid,
  • Hydrobromic acid sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, acetic acid, tartaric acid, malic acid, embonic acid, malonic acid, trifluoroacetic acid or maleic acid.
  • the compounds of the formula (1) according to the invention can, if desired, be in their salts with inorganic or organic bases, in particular for pharmaceutical use in their physiological tolerable salts.
  • bases which can be used here are sodium hydroxide, potassium hydroxide, calcium hydroxide, lysine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • pyridine derivatives according to general formula 1 are provided, in which R, R1, R2, R3, X, Z, P, Q, n and m have the meanings given above and
  • R 4 is a straight-chain or branched (-CC 2 o) -alkyl radical which can be saturated or unsaturated with one to three double and / or triple bonds and which is unsubstituted or optionally on the same or different C atoms, two or more aryl, heteroaryl, halogen, (C1-C6) alkoxy, amino, mono- (CC 4 ) alkylamino or di- (C1-C4) alkylamino may be substituted;
  • a phenyl radical or a naphthyl radical each unsubstituted or one or more of the same or different with straight-chain or branched (-C-C 8 ) alkyl, (C 3 -C 7 ) cycloalkyl, halogen, cyano, ( C ⁇ -C 6 ) - Alkoxycarbonylamino, (C ⁇ -C6) alkoxy, carboxy, (C ⁇ -C ⁇ ) alkoxycarbonyl, with one or more fluorine atoms substituted straight-chain or branched (C ⁇ -C ⁇ ) alkyl, preferably trifluoromethyl, hydroxy, straight-chain or branched (-C-Cs) alkoxy, preferably methoxy or ethoxy, where adjacent oxygen atoms can also be linked by (-C-C 2 ) alkylene groups, preferably a methylene group, benzyloxy, nitro, amino, mono-CrC ⁇ -Alkylamino,
  • Aryl which in turn is unsubstituted or one or more identical or different with straight-chain or branched (C ⁇ -C ⁇ ) alkyl, (C3-C7) cycloalkyl, carboxy, straight-chain or branched (C ⁇ -C ⁇ ) alkoxycarbonyl, with trifluoromethyl, Hydroxy, straight-chain or branched (-CC 8 ) alkoxy, preferably methoxy or ethoxy, benzyloxy, nitro, amino, mono- (-C-C4)
  • Alkylamino, di (C 1 -C 4 ) alkylamino, cyano, straight-chain or branched cyano (C 1 -C 6 ) alkyl is substituted can be substituted, a 2-, 4-, 5- or 6-pyrimidinyl radical or 2-, 4-, 5- or 6-pyrimidinyl- (Ci -C 4 ) alkyl radical, where the (Ci -C4) alkyl ⁇
  • Halogen nitro, amino, mono- (-C-C 6 ) alkylamino, di- (C ⁇ -C 6 ) alkylamino, hydroxy, (Ci-CeJ-alkoxy, benzyloxy, carboxy, (CrC 6 ) -alkoxycarbonyl, (C ⁇ -C 6 ) alkoxycarbonylamino or mono- or polysubstituted with fluorine (Ci -C 6 ) alkyl, preferably trifluoromethyl, (C 6 -C ⁇ o) aryl, or (C 6 -C ⁇ 0 ) aryl (Ci-C ⁇ J alkyl may be substituted;
  • (-C-C 6 ) alkyl halogen, nitro, amino, mono- (C ⁇ -C 6 ) alkylamino, di- (CrC 6 ) alkylamino, hydroxy, (C ⁇ -C ⁇ ) alkoxy, benzyloxy, carboxy, ( Ci-C ⁇ ) - alkoxycarbonyl, (-C-Ce) -alkoxycarbonylamino or one or more fluorine-substituted (Ci -C ⁇ J-alkyl, preferably trifluoromethyl, (C 6 -C 1 o) aryl, or (C 6 - C ⁇ o) aryl (C ⁇ -C ⁇ ) alkyl may be substituted;
  • a 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl radical or 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl- (C ⁇ - C 4) -alkyl radical, where the (Ci-C4) -alkyl radical can be unsubstituted or mono- or polysubstituted by identical or different (Ci -C ⁇ ) alkyl, halogen or oxo ( O) may be substituted and the 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl
  • Radical is unsubstituted or mono- to hexasubstituted by identical or different hydrogen, (C- ⁇ -C ⁇ ) alkyl, preferably methyl, particularly preferably 2-methyl, halogen, nitro, amino, mono- (dC 6) alkylamino, di- (-CC 6 ) - alkylamino, hydroxy, (-C-C ⁇ ) alkoxy, benzyloxy, carboxy, (Ci-C ⁇ ) - alkoxycarbonyl, (-C-C 6 ) alkoxycarbonylamino or one or more times with
  • Fluorine-substituted (Ci -C ⁇ ) alkyl preferably trifluoromethyl, (C 6 -C ⁇ o) aryl, or (C 6 -C ⁇ o) aryl (C ⁇ -C 6 ) alkyl may be substituted;
  • Carboxy, (-C-C ⁇ ) alkoxycarbonyl, (CrC ⁇ J-alkoxycarbonylamino or (C 1 -C 6 ) alkyl substituted one or more times with fluorine, preferably trifluoromethyl, (C 6 -C ⁇ o) aryl, or (C 6 -C ⁇ o) -Aryl- (-C-C6) alkyl may be substituted; a 2-, 6-, 8- or 9- [9H] -urinyl residue or 2-, 6-, 8- or 9- [9H] -purinyl- (Ci-C4) -alkyl residue, where the ( Ci -C 4 ) alkyl radical unsubstituted or substituted one or more times, identically or differently, with (Ci -C ⁇ ) alkyl, halogen or oxo ( 0) and which is 2-, 6-, 8- or 9- [9H] -Purinyl residue unsubstituted or mono-
  • (d-C ⁇ ) alkyl may be substituted
  • (Ci -C 6 ) alkyl preferably trifluoromethyl, (C 6 -C ⁇ o) aryl, or (C 6 -do) aryl- (d-C ⁇ ) alkyl may be substituted;
  • a 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl or 1-, 2-, 3-, 4-, 5-, 6-, 7- , 8- or 9-acridinyl- (-C -C 4 ) alkyl radical, where the (Ci -C6) alkyl radical is unsubstituted or one or more times the same or different with (Ci -C ⁇ ) - alkyl, halogen or Oxo ( 0) can be substituted and the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl residue unsubstituted or one to eight times the same or different with hydrogen , (dC ⁇ ) -alkyl, halogen, nitro, amino, mono- (d-C ⁇ ) -alkylamino, di- (-C-C B ) -alkylamino, hydroxy, (C ⁇ -C 6 ) -alkoxy,
  • a 2-, 3-, -4-, 5, - or 6-pyridyl radical where the 2-, 3 -, - 4-, 5, - or 6-pyridinyl radical is unsubstituted or one to four times the same or different with hydrogen, (-CC 6 ) -alkyl, halogen, nitro, amino, mono- (-C-C 6 ) -alkylamino, di- (-C-C 6 ) -alkylamino, hydroxy, (CrC 6 ) -alkoxy, Benzyloxy, carboxy, (-CC 6 ) - alkoxycarbonyl, (-CC 6 ) alkoxycarbonylamino or one or more times
  • Fluorine substituted (Ci -C 6 ) alkyl preferably trifluoromethyl, (C ⁇ -C ⁇ o) aryl, or (C ⁇ -C ⁇ o) aryl (C ⁇ -C ⁇ ) alkyl may be substituted;
  • (-C-C ⁇ ) alkyl may be substituted
  • Alkyl preferably trifluoromethyl, (C ⁇ -C ⁇ o) aryl, or (C ⁇ -C ⁇ o) aryl- (C ⁇ -C6) - alkyl can be substituted;
  • Benzthiazolyl radical unsubstituted or one to four times the same or different with hydrogen, (-CC 6 ) alkyl, halogen, nitro, amino, mono- (-C-C 6 ) - alkylamino, di- (-C-C 6 ) - Alkylamino, hydroxy, (-C-C 6 ) alkoxy, benzyloxy, carboxy, (dC ⁇ ) alkoxycarbonyl, (CrC ⁇ ) alkoxycarbonylamino or mono- or polysubstituted with fluorine (Ci -C 6 ) alkyl, preferably trifluoromethyl,
  • (Ci -C 6 ) alkyl preferably trifluoromethyl, (C 6 -C ⁇ o) aryl, or (C 6 -C ⁇ o) aryl (C ⁇ -C ⁇ ) alkyl may be substituted;
  • (dC ⁇ ) alkyl may be substituted
  • Fluorine-substituted (Ci-C ⁇ ) alkyl preferably trifluoromethyl, (C 6 -C ⁇ o) aryl, or (C ⁇ -C ⁇ o) aryl- (-C-C ⁇ ) alkyl may be substituted;
  • Alkoxycarbonylamino or mono- or polysubstituted with fluorine (Ci -C ⁇ ) - alkyl, preferably trifluoromethyl, (C 6 -C ⁇ o) aryl, or (C 6 -C ⁇ o) aryl (C ⁇ -C ⁇ ) - alkyl can be substituted ; a 1- or 5- [1H] tetrazolyl radical or 1- or 5- [1H] tetrazolyl- (-C -C ⁇ ) - alkyl radical, the (Ci -C ⁇ ) alkyl radical being unsubstituted or a - or several times the same or different with (Ci -C ⁇ ) alkyl, halogen or oxo ( 0) and the 1 - or 5- [1 H] tetrazolyl radical may be unsubstituted or substituted
  • (d-C ⁇ ) alkyl may be substituted
  • Fluoro-substituted (Ci-C6) alkyl preferably trifluoromethyl, (C6 -C ⁇ o) aryl, or (C 6 -C ⁇ o) aryl (C ⁇ -C6) alkyl may be substituted; means and the isomers, in particular tautomers, diastereomers and enantiomers, and the pharmaceutically acceptable salts, in particular acid addition salts thereof.
  • pyridine derivatives according to the general formula (1) are provided, characterized in that R, R 1, R 2 , R 3 , X, Z, P, Q, n and m have the abovementioned meanings and R 4 is phenyl stands, which is unsubstituted or substituted with one to five identical or different (-CC 6 ) alkoxy groups, adjacent oxygen atoms may also be linked by (-C-C2) alkylene groups.
  • pyridine derivatives according to the general formula (1) are provided, characterized in that R 4 has the meanings given above, R, R1, R2, R3 each represent a hydrogen atom, Z represents an oxygen atom and X represents a nitrogen atom , P and Q each represent two hydrogen atoms (i.e. -CH2-), m is zero and n represents the integer 2.
  • pyridine derivatives according to the general formula (1) are provided, characterized in that R, R 1 , R 2 , R 3 , X, Z, P, Q, n and m have the meanings given above and R 4 represents 3,5-dimethoxyphenyl.
  • pyridine derivatives according to the general formula (1) are provided, characterized in that R, R 1 , R 2 , R3 each for a hydrogen atom, Z for an oxygen atom, X for a nitrogen atom, P and Q each for two hydrogen atoms (i.e. -CH2-) stand, m is zero, n stands for the integer 2 and R 4 stands for a 3,5-dimethoxyphenyl radical.
  • Z represents an oxygen or sulfur atom and Y for a leaving group such as halogen, hydroxy, (C1-C6) alkoxy preferably methoxy and ethoxy, -0-tosyl, -O Mesyl or imidazolyl, with an amine of the general formula (3),
  • R4, X, P, Q, m and n have the meanings given above, if appropriate using diluents and auxiliaries to form the desired pyridine derivative.
  • the starting compounds (2) and (3) are either commercially available or can be prepared by processes known per se.
  • the starting materials (2) and (3) are valuable intermediates for the preparation of the pyridine derivatives of the formula (1) according to the invention.
  • reaction temperature and reaction time are known from the literature or are known to the person skilled in the art on the basis of his specialist knowledge.
  • the pyridine derivatives according to the invention according to the general formula (1) are suitable as medicaments, in particular as antitumor agents, for the treatment of mammals, in particular humans, but also for pets such as horses, cows, dogs, cats, rabbits, sheep, poultry and the like ,
  • a method for combating tumors in mammals which is characterized in that at least one pyridine derivative according to the general formula (1) is administered to a mammal in an amount effective for tumor treatment.
  • the therapeutically effective dose of the respective pyridine derivative according to the invention to be administered for the treatment depends, inter alia, on the type and stage of the tumor disease, the age and sex of the patient, the type of administration and the duration of the treatment. Administration can be oral, rectal, buccal (eg sublingual), parenteral (eg subcutaneous, intramuscular, intradermal or intravenous), topical or transdermal.
  • Tumor treatment which are characterized in that they contain at least one pyridine derivative according to one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient, optionally together with customary pharmaceutically acceptable auxiliaries, additives and carriers.
  • These can be solid, semi-solid, liquid or aerosol preparations.
  • Suitable solid preparations are, for example, capsules, powders, granules, tablets.
  • Suitable semi-solid preparations are, for example, ointments, creams, gels, pastes, suspensions, oil-in-water and water-in-oil emulsions.
  • Suitable liquid preparations are, for example, sterile aqueous preparations for parenteral administration which are isotonic with the patient's blood.
  • the substance D-43411 was tested for its anti-proliferative activity in a proliferation test on established tumor cell lines.
  • the test used determines the cellular dehydrogenase activity and enables a determination of the cell vitality and indirectly the cell number.
  • the cell lines used are the human cervical carcinoma cell line KB / HeLa (ATCC CCL17), the murine lymphocytic leukemia L1210 (ATCC CCL-219), the human breast adenocarcinoma line MCF7 (ATCC HTB22) and the ovarian adenocarcinoma line SKOV-3 (ATCC CCB17) ). These are very well characterized, established cell lines obtained from ATCC and taken in culture.
  • the adherent growing tumor cell lines HeLa / KB, SKOV-3 and MCF7 as well as the L1210 leukemia line growing in suspension were cultivated under standard conditions in the gassing incubator at 37 ° C, 5% C0 2 and 95% humidity.
  • the adherent cells are detached with trypsin / EDTA and pelleted by centrifugation.
  • the cell pellet is then resuspended in the RPMI culture medium in the appropriate cell number and converted into a 96-well microtiter plate.
  • the plates are then cultivated overnight in the fumigation incubator.
  • the test substances are prepared as stock solutions in DMSO and diluted with culture medium in the appropriate concentrations on test day 2.
  • the substances in culture medium are then added to the cells and incubated for 45 hours in the fumigation incubator. Cells that are not treated with test substance serve as a control.
  • XTT sodium 3 '- [1- (phenylaminocarbonyl) -3,4-tetrazolium] bis (4-methoxy-6-nitro) benzenesulfonic acid
  • RPMI-1640 medium without phenol red
  • PMS N-methyl dibenzopyrazine methyl sulfate
  • PBS phosphate-buffered saline
  • the XTT solution is mixed with the PMS solution in a ratio of 50: 1 (vol: vol) shortly before use.
  • the cell plates are then incubated in the gassing incubator for a further 3 hours and the optical density (OD4gonm) is determined in the photometer.
  • the percentage inhibition relative to the control is calculated using the determined OD49onm.
  • the anti-proliferative effect is estimated using a regression analysis.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing. This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.
EP01960509A 2000-07-21 2001-07-18 Neue heteroaryl-derivate und deren verwendung als antitumormittel Withdrawn EP1305289A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10035908 2000-07-21
DE10035908A DE10035908A1 (de) 2000-07-21 2000-07-21 Neue Heteroaryl-Derivate und deren Verwendung als Arzneimittel
PCT/EP2001/008262 WO2002008190A2 (de) 2000-07-21 2001-07-18 Neue heteroaryl-derivate und deren verwendung als antitumormittel

Publications (1)

Publication Number Publication Date
EP1305289A2 true EP1305289A2 (de) 2003-05-02

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Application Number Title Priority Date Filing Date
EP01960509A Withdrawn EP1305289A2 (de) 2000-07-21 2001-07-18 Neue heteroaryl-derivate und deren verwendung als antitumormittel

Country Status (21)

Country Link
US (1) US6638935B2 (hu)
EP (1) EP1305289A2 (hu)
JP (1) JP2004516243A (hu)
KR (1) KR20030015894A (hu)
CN (1) CN1447796A (hu)
AR (1) AR032467A1 (hu)
AU (2) AU8198901A (hu)
BG (1) BG107506A (hu)
BR (1) BR0112711A (hu)
CA (1) CA2353353A1 (hu)
DE (1) DE10035908A1 (hu)
HU (1) HUP0300743A2 (hu)
IL (1) IL153931A0 (hu)
MX (1) MXPA03000596A (hu)
NO (1) NO20030302L (hu)
NZ (1) NZ524156A (hu)
PL (1) PL361354A1 (hu)
RU (1) RU2003105238A (hu)
SK (1) SK1942003A3 (hu)
WO (1) WO2002008190A2 (hu)
ZA (1) ZA200300545B (hu)

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PL361354A1 (en) 2004-10-04
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WO2002008190A2 (de) 2002-01-31
BR0112711A (pt) 2003-05-20
CN1447796A (zh) 2003-10-08
NO20030302D0 (no) 2003-01-20
SK1942003A3 (en) 2003-12-02
AU2001281989B2 (en) 2005-05-12
KR20030015894A (ko) 2003-02-25
US20020111354A1 (en) 2002-08-15
HUP0300743A2 (hu) 2003-10-28
JP2004516243A (ja) 2004-06-03
BG107506A (bg) 2003-09-30
US6638935B2 (en) 2003-10-28
NZ524156A (en) 2005-10-28
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IL153931A0 (en) 2003-07-31
DE10035908A1 (de) 2002-03-07
RU2003105238A (ru) 2004-08-10
ZA200300545B (en) 2003-02-12
NO20030302L (no) 2003-02-07
AR032467A1 (es) 2003-11-12
CA2353353A1 (en) 2002-01-21

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