WO2006018117A1 - Substituierte 8-aminoalkoxi-xanthine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel - Google Patents
Substituierte 8-aminoalkoxi-xanthine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel Download PDFInfo
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- WO2006018117A1 WO2006018117A1 PCT/EP2005/008283 EP2005008283W WO2006018117A1 WO 2006018117 A1 WO2006018117 A1 WO 2006018117A1 EP 2005008283 W EP2005008283 W EP 2005008283W WO 2006018117 A1 WO2006018117 A1 WO 2006018117A1
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- alkyl
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- heterocyclyl
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- 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
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- 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
- A61P3/06—Antihyperlipidemics
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- 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
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- 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
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- 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
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- 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
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the invention relates to substituted 8-aminoalkoxi-xanthines and their physiologically acceptable salts and physiologically functional derivatives.
- the invention had the object of providing compounds that develop a therapeutically useful blood sugar lowering effect. These compounds should be particularly suitable for the treatment of diabetes.
- the invention therefore relates to compounds of the formula I,
- Rl, R2, R3 are independently H, (Ci-C] 0) alkyl, (C 3 -C 0) cycloalkyl, (C 2 -C 10) - alkenyl, (C 2 -C i O) alkynyl, (C 6 -C) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2 , SF 5 , OH, (Ci-C 6 ) -
- R7, R8 are independently H, (Ci-C 6) -alkyl, (C 3 -C 10) cycloalkyl, (C 6 -C 0) aryl,
- R9, RIO each independently H, (C r C6) alkyl, (Ci-C 6) alkylene- (C 6 -d 0) aryl, (Ci- C 6) -alkylene-heterocyclyl;
- R 4 is hydrogen, (C r C 6 ) -alkyl or (C 3 -C 8 ) -cycloalkyl, where (C 1 -C 6 ) -alkyl or
- (C 3 -C 8 ) -cycloalkyl may be substituted with F, Cl, Br, I, CN, aryl, heterocyclyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((C, -C 6 ) alkyl) 2, OH, O (dC 6) alkyl, O-aryl, OHeteroaryl, S (dC 6) alkyl, S (O) (Ci-C6) - alkyl, S (O) 2 (Ci-C 6 ) -Alkyl, wherein the respective alkyl groups with F, Cl, Br, I can be substituted and wherein the aryl and Heterocyclylreste can each be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2 , SF 5 , OH, (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3 , - S
- R 12, R 13, R 14, R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, aryl, heterocyclyl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 4 ) -alkylene-O-alkyl , (C 1 -C 4 ) -alkylene-SAlkyl, (C 1 -C 4 ) -
- (C, -C 6) -alkyl, SO 2 - (C 3 -C 6) -cycloalkyl, SO 2 -NH 2, SO 2 -NH- (C, -C6) - alkyl, SO 2 - NH-SO 2 - (C 3 -C 6 ) -cycloalkyl may be substituted; where the aryl and Heterocyclyl may be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2 , SF 5 , OH, (CC ⁇ alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6) - alkenyl, (C 2 - C 6) alkynyl, 0 (C 1 -C 4) - alkyl, NH 2, NH (C 1 -C 4) - alkyl, NKQ-C ⁇ alkyl) ⁇ NR7CONH ( C, -C
- n O or 1;
- Rl, R2, R3 are independently H, (C r C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C] 0) alkynyl, ( C 6 -C i O) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, I, CN, NO 2 , SF 5 , OH, (C 1 -C 6 ) alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, 0R7 , OP (O) (OR7) 2 , NR7R8, NR7CONR7R8, C0R7
- R 7, R 8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 6 -C 10 ) -aryl,
- R9, RIO each independently H, (Ci-C 6) -alkyl, (Ci-C 6) alkylene- (C 6 -C 0) aryl, (C 1 - C 6) -alkylene-heterocyclyl;
- R 4 is hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 8 ) -cycloalkyl, where (C 1 -C 6 ) -alkyl or
- (C 3 -C 8 ) -Cycloalkyl may be substituted with F, Cl, Br, I, CN, aryl, heterocyclyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl ) 2 , OH, O (C 1 -C 6 ) -alkyl, O-aryl, OHeteroaryl, S (C 1 -C 6 ) -alkyl, S (O) (C 1 -C 6 ) -alkyl, S (O) 2 (C 1 -C 4 ) -alkyl, C 6 ) alkyl; where the aryl and heterocyclyl radicals may be mono- or polysubstituted by F, Cl, Br, I, CN, NO 2 , SF 5 , OH, (C 1 -C 6 ) -alkyl, -CF 3 , -OCF 3
- n O or 1;
- Rl, R2, R3 are independently H, (Ci-Cio) alkyl, (C 3 -C 10) cycloalkyl, (C 2 -C 0) - alkenyl, (C 2 -C 10) -alkynyl, (C 6 -Ci 0 ) aryl, heterocyclyl, where the alkyl, Cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted by F, Cl, Br, I, CN, NO 2 , SF 5 , OH, (C 1 -C 6 ) -alkyl, CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, OR 7, OP (O) (OR 7) 2 , NR 7 R 8, NR 7CONR 7 R 8, COR
- R7, R8 are independently H, (Ci-C 6) -alkyl, (C 3 -C 0) cycloalkyl, aryl,
- R 4 is hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 8 ) -cycloalkyl, where (C 1 -C 6 ) -alkyl or
- (C 3 -C 8 ) -cycloalkyl may be substituted with F, Cl, Br, I, CN, aryl, heterocyclyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((C, -C 6 ) alkyl) 2, OH, O (Ci-C 6) -alkyl, O-aryl, OHeteroaryl, S (C r C6) alkyl, S (O) (C-C6) - alkyl, S (O) 2 (C 1 -C 6 ) -alkyl;
- R 1, R 12, R 13, R 14, R 15, R 16 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, (C 1 -C 4 ) -alkylene-aryl or (C 1 -C 4 ) -alkylene-heterocyclyl;
- R 4 or two of the radicals R 4, R 11, R 12, R 13, R 14, R 15, R 16 together form a (C 2 -C 6 ) -alkylene radical;
- R 1, R 2, R 3, independently of one another, are (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, (C 2 -C 10 ) -alkenyl, (C 2 -C 10 ) -alkynyl, (C 6 - C 10 ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be mono- or polysubstituted with F, Cl, Br, CN, NO 2 , SF 5 , OH , (C 1 -C 6) - alkyl, -CF 3, -OCF 3, - SCF 3, (C 2 -C 6) - alkenyl, (C 2 -C 6) - alkynyl, OR7, NR7R8, NR7CONR7R8,
- R2 and R3 may be methyl at the same time
- R7, R8 are independently H, (Ci-C6) - alkyl, (C 3 -C 0) cycloalkyl, aryl,
- Heterocyclyl C 1 -C 4 -alkylene C 1 -C 4 -aryl or (C 1 -C 4 ) -alkylene heterocyclyl;
- R4 is hydrogen
- R 1, R 12, R 13, R 14 independently of one another are H, (C 1 -C 6 ) -alkyl or C 3 -C 7 -cycloalkyl,
- Rl, R2, R3 are independently (Ci-C 6) -alkyl, (C 3 -C 0) cycloalkyl, (C 2 -C 10) alkenyl, (C 2 -C 10) -alkynyl, (C 6 - C i O ) -aryl, heterocyclyl, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocyclyl radicals may be monosubstituted or polysubstituted with F, Cl, CN, SF 5 , (Ci-C 6 ) - alkyl, -CF 3 , -OCF 3 , -SCF 3 , (C 2 -C 4) -
- R7, R8 independently of one another are H, (C 1 -C 6 ) -alkyl, (C 3 -C 10 ) -cycloalkyl, aryl, heterocyclyl, (C 1 -C 4 ) -alkylene- (C 6 -C 10) -aryl or (C 1 -C 4 ) -alkylene
- R4 is hydrogen
- Rl 1, R12, R13, R14 independently of one another H, (C r C4) - alkyl
- the invention relates to compounds of the formula I, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
- radicals or substituents can occur several times in the compounds of the formula I, they may all independently of one another have the meanings indicated and be identical or different.
- Pharmaceutically acceptable salts are particularly suitable for medical applications because of their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation.
- Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and also organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric acid.
- Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-l, 3-propanediol), diethanolamine, lysine, or ethylenediamine.
- Salts with a non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example, in vitro applications.
- physiologically functional derivative refers to any physiologically acceptable derivative of a compound of formula I, e.g. an ester which, when administered to a mammal, e.g. humans, is able to form (directly or indirectly) a compound of formula I or an active metabolite thereof.
- the physiologically functional derivatives also include prodrugs of the compounds according to the invention.
- prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may or may not be effective.
- the compounds according to the invention can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention.
- all references to "compound (s) according to formula I" refer to compounds of the formula I as described above, and their salts, solvates and physiologically functional derivatives as described herein.
- alkyl radical is meant a straight or branched hydrocarbon chain having one or more carbons, e.g. Methyl, ethyl, iso-propyl, tert-butyl, hexyl.
- the alkyl radicals may be mono- or polysubstituted by suitable groups, such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH ( C, -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2i cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, O- (C, -C 6 ) - alkyl -O-CO- (! C-C6) - alkyl, 0-CO- (Ci-C6) - aryl, O-CO- (C r C6) -heterocycle ,;
- suitable groups such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1
- alkenyl radical is understood to mean a straight-chain or branched hydrocarbon chain having two or more carbons and one or more double bonds, such as, for example, vinyl, AIII, pentenyl.
- the alkenyl radicals may be monosubstituted or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH ( Ci -C 6) alkyl, CONt (C 1 -C 6) AUCyI] 2, cycloalkyl, (C, -C10) - alkyl, (C 2 -C 6) -alkynyl, 0- (Ci-C6) - alkyl O-CO- (Ci-C 6) -alkyl, 0-CO- (C J-C6) - aryl, O-CO- (dC 6) -heterocycle
- alkynyl radical is meant a straight or branched hydrocarbon chain having two or more carbons and one or more triple bonds, e.g. Ethynyl, propynyl, hexynyl.
- the alkynyl radicals may be monosubstituted or polysubstituted by suitable groups, such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH ( C, -C 6) alkyl, CON [(C, -C 6) alkyl] 2, cycloalkyl, (C 2 -C 6) - alkenyl, (C-C10) - alkyl, 0- (Ci-C6 ) - alkyl O-CO- (C 1 -C 6 ) -alkyl, O-CO- (C 1 -C 6 ) -aryl, O-CO- (C 1 -C 6 ) -heterocycle;
- suitable groups such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (
- aryl radical is understood as meaning a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralonic, indanyl or indan-1-onyl radical.
- the aryl radicals may be monosubstituted or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2; Cycloalkyl, (C 1 -C 10 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, O- (C 1 -C 6 ) -alkyl O-CO- (C] - C 6 ) alkyl, 0-CO- (C 1 -Co) -acyl, O-CO- (C r C 6 ) -heterocycle; PO 3 H 2, SO 3 H, SO 2 -NH 2, SO 2 NH (Ci-C 6)
- a cycloalkyl radical is to be understood as meaning a ring system containing one or more rings which is saturated or partially unsaturated (having one or two double bonds), which is composed exclusively of carbon atoms, for example cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
- the cycloalkyl radicals may be monosubstituted or polysubstituted by suitable groups such as: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 - C 6) alkyl, CONC (C 1 -C 6) AUCyI] 2, cycloalkyl, (C 1 -Co) -alkyl, (C 2 -C 6) alkenyl, (C 2 -C 6) - alkynyl, 0- (C, -C 6) - alkyl 0-CO- (Ci-C6) - alkyl, 0-CO- (Ci-C6) - aryl, 0-CO- (C r C6) - heterocycle ,; PO 3 H 2 , SO 3 H, SO 2 -NH 2 , SO 2 NH (C 1 -C 6 ) -al
- Heterocyclyl or heterocyclic radical is understood to mean rings and ring systems which, in addition to carbon, also contain heteroatoms, such as, for example, nitrogen, oxygen or sulfur. Furthermore, ring systems also belong to this definition, in which the heterocyclic or the heterocyclic radical is condensed with benzene nuclei.
- Suitable heterocyclic rings, heterocyclyl or heterocyclic radicals are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H- Quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furyl, furazanyl, imid
- Pyridyl is both 2-, 3- and 4-pyridyl.
- Thienyl is both 2- and 3-thienyl.
- Furyl is both 2- and 3-furyl.
- N-oxides of these compounds e.g. l-oxi-2-, 3- or 4-pyridyl.
- heterocyclic rings, heterocyclyl or heterocyclic radicals may be monosubstituted or polysubstituted by suitable groups, such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C r C 6 ) alkyl, CONH 2, CONH (C 1 -C 6) alkyl, CON [(C 1 -C 6) alkyl] 2, cycloalkyl, (C 1 -C O) -AUCyI, (C 2 -C 6) alkenyl, (C 2 -C 6) -alkynyl, 0- (C, -C 6) - alkyl O-CO- (C 1 -C 6) alkyl, O- CO-TCRC ⁇ aryl.
- suitable groups such as, for example: F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO (C r C 6 )
- the compound (s) of formula (I) may also be administered in combination with other active ingredient.
- the daily dose is in the range of 0.3 mg to 100 mg (typically 3 mg and 50 mg) per day per kilogram of body weight, eg 3-10 mg / kg / day.
- an intravenous dose may range from 0.3 mg to 1.0 mg / kg, which may conveniently be administered as an infusion of 10 ng to 100 ng per kilogram per minute.
- Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter.
- Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
- vials for injections, and orally administrable unit dose formulations, such as tablets or capsules may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg.
- the compounds according to formula I can themselves be used as compound, but they are preferably present with a tolerable carrier in the form of a pharmaceutical composition.
- the carrier must, of course, be compatible, in the sense that it is compatible with the other ingredients of the composition and is not harmful to the health of the patient.
- the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
- Other pharmaceutically active substances may likewise be present, including further compounds of the formula I.
- the pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the ingredients with pharmacologically acceptable carriers and / or excipients ,
- compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable administration in each individual case is of the type and The severity of the condition to be treated and the type of compound used in each case according to formula I is dependent. Also coated formulations and coated slow release formulations are within the scope of the invention. Preference is given to acid and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate,
- Hydroxipropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate are examples of hydroxyethacrylate and hydroxyethacrylate.
- Suitable pharmaceutical compounds for oral administration may be in separate units, such as capsules, cachets, lozenges or tablets, each containing a certain amount of the compound of formula I; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid ness; or as an oil-in-water or water-in-oil emulsion.
- these compositions may be prepared by any suitable pharmaceutical method comprising a step of contacting the active ingredient and the carrier (which may consist of one or more additional ingredients).
- the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is molded if necessary.
- a tablet can be produced by compressing or molding a powder or granules of the compound, if appropriate with one or more additional constituents.
- Compressed tablets can be prepared by tableting the compound in free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant in a suitable machine. Molded tablets may be prepared by shaping the powdered compound moistened with an inert liquid diluent in a suitable machine.
- compositions suitable for peroral (sublingual) administration include lozenges containing a compound of Formula I with a flavor, usually sucrose and gum arabic or tragacanth, and lozenges containing the compound in an inert Base such as gelatin and glycerin or sucrose and gum arabic.
- Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula I which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although the administration may also be subcutaneous, intramuscular or intradermal as an injection. These preparations can preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1% to 5% by weight of the active compound. Suitable pharmaceutical compositions for rectal administration are preferably present as single-dose suppositories. These can be prepared by mixing a compound according to formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
- Suitable pharmaceutical compositions for topical application to the skin are preferably as an ointment, cream, lotion, paste, spray, aerosol or oil.
- Vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances can be used as the carrier.
- the active ingredient is generally present at a level of from 0.1% to 15% by weight of the composition, for example from 0.5% to 2%.
- Suitable pharmaceutical compositions for transdermal applications may be present as individual patches suitable for long-term close contact with the epidermis of the patient.
- patches suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer.
- a suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%.
- the active ingredient can be released by electrotransport or iontoforesis as described, for example, in Pharmaceutical Research, 2 (6): 318 (1986).
- the administration of the active ingredient combination can be carried out either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation.
- Most of the drugs listed below are disclosed in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.
- Antidiabetics include insulin and insulin derivatives, such as Lantus ® (see www.lantus.com) or HMR 1964 fast-acting insulins (see US No. 6,221,633), GLP-I derivatives such as those described in WO 98/08871 of Novo Nordisk A / S, as well as orally active hypoglycemic agents.
- the orally active hypoglycemic agents preferably include sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers such as those described in WO 97/26265 and WO 99/03861 of Novo Nordisk A / S, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake, fat metabolism altering compounds such as antihyperlipidemic agents and antilipidemic agents, compounds that reduce food intake, PPAR and PXR agonists and drugs that act on the ATP-dependent potassium channel of beta cells.
- the compounds of formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
- an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
- the compounds of formula I are administered in combination with a cholesterol resorption inhibitor, e.g. Ezetimibe, Tiqueside, Pamaqueside, or with a compound as described in PCT / EP 2004/00269, PCT / EP 2003/05815, PCT / EP 2003/05814, PCT / EP 2003/05816, EP 0114531, US Pat. No. 6,498,156.
- a cholesterol resorption inhibitor e.g. Ezetimibe, Tiqueside, Pamaqueside
- the compounds of formula I are administered in combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
- a PPAR gamma agonist e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.
- the compounds of the formula I are administered in combination with PPAR alpha agonist, such as, for example, GW 9578, GW 7647.
- PPAR alpha agonist such as, for example, GW 9578, GW 7647.
- the compounds of formula I are used in combination with a mixed PPAR alfa / gamma agonist such as GW 1536, AVE 8042, AVE 8134, AVE 0847 or as in PCT / US 2000/11833, PCT / US 2000 / 11490, DE10142734.4.
- the compounds of formula I are used in combination with a fibrate, e.g. Fenofibrate, clofibrate, bezafibrate.
- a fibrate e.g. Fenofibrate, clofibrate, bezafibrate.
- the compounds of formula I are administered in combination with an MTP inhibitor, e.g. Implitapide, BMS-201038, R-103757.
- an MTP inhibitor e.g. Implitapide, BMS-201038, R-103757.
- the compounds of formula I are used in combination with bile acid resorption inhibitor (see for example US 6,245,744 or US 6,221,897), e.g. HMR 1741 administered.
- the compounds of formula I are administered in combination with a CETP inhibitor, e.g. JTT-705.
- a CETP inhibitor e.g. JTT-705.
- the compounds of formula I are used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam.
- a polymeric bile acid adsorber e.g. Cholestyramine, colesevelam.
- the compounds of formula I are used in combination with an LDL receptor inducer (see US 6,342,512), e.g. HMRI 171, HMR 1586 administered.
- an LDL receptor inducer see US 6,342,512
- HMRI 171, HMR 1586 administered e.g. HMRI 171, HMR 1586 administered.
- the compounds of the formula I are administered in combination with an AC AT inhibitor, such as avasimibe. In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, such as OPC-14117.
- the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, e.g. NO-1886, administered.
- a lipoprotein lipase inhibitor e.g. NO-1886
- the compounds of formula I are used in combination with an ATP citrate lyase inhibitor, e.g. SB-204990 administered.
- the compounds of formula I in combination with a squalene synthetase inhibitor, such as e.g. BMS 188494 administered.
- a squalene synthetase inhibitor such as e.g. BMS 188494 administered.
- the compounds of formula I in combination with a lipoprotein (a) antagonist, such as. CI-1027 or nicotinic acid.
- a lipoprotein (a) antagonist such as. CI-1027 or nicotinic acid.
- the compounds of formula I are used in combination with a lipase inhibitor, e.g. Orlistat, administered.
- a lipase inhibitor e.g. Orlistat
- Sulfonylurea e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
- the compounds of formula I are used in combination with a biguanide, e.g. Metformin, administered.
- a biguanide e.g. Metformin
- the compounds of formula I in combination with a meglitinide, e.g. Repaglinide, administered.
- a meglitinide e.g. Repaglinide
- the compounds of the formula I in combination with a Thiazolidindion such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, especially 5 - [[4- [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione.
- a Thiazolidindion such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, especially 5 - [[4- [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione.
- the compounds of formula I are administered in combination with an ⁇ -glucosidase inhibitor, e.g. Miglitol or acarbose, administered.
- an adenosine Al agonists such as.
- the compounds of formula I are administered in combination with an agent which acts on the ATP-dependent potassium channel of the beta cells, e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
- an agent which acts on the ATP-dependent potassium channel of the beta cells e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
- the compounds of formula I are used in combination with more than one of the aforementioned compounds, e.g. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
- the compounds of the formula I are used in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript-influenced transient influenza energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M .: Hormones and Metabolism Research (2001), 33 (9), 554-558), NPY antagonists eg naphthalene-1-sulfonic acid ⁇ 4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl ⁇ -amide hydrochloride ( CGP 71683A)), MC4 agonists (eg 1-amino-l, 2,3,4-tetrahydro-naphthalene-2-carboxylic acid [2- (3-a-benzyl-2-methyl-3-oxo-2,3, 3 a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl)
- CART modulators
- the further active ingredient is leptin; see, e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi,
- the other active ingredient is dexamphetamine or amphetamine.
- the other active ingredient is fenfluramine or dexfenfluramine.
- the other active ingredient is sibutramine.
- the other active ingredient is orlistat.
- the other active ingredient is mazindol or phentermine.
- the other active ingredient is rimonabant.
- the compounds of formula I in combination with bulking agents preferably insoluble bulking agents (see, for example, carob / Caromax ® (Zunft HJ; et al, Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN.
- Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark availability, 65926 Frankfurt / Main)). Combination with Caromax ® is possible in one preparation or by separate administration of compounds of the formula I and Caromax ®. Caromax can also be administered in the form of foods such as baked goods or muesli bars.
- the compounds of the formula I can be prepared by suitable starting materials of the formula II, wherein R 1, R 2 and R 3 have the abovementioned meaning and X is a leaving group, such as chlorine, bromine, iodine, sulfonyloxy, sulfinyl, sulfoxil, with a compound of formula III wherein M is a metal such as lithium, sodium, potassium, cesium, magnesium, calcium, etc., optionally in the presence of suitable bases in inert solvents to the compounds of formula I.
- the starting materials of the formula II can be reacted with alcohols of the formula III in which M has the meaning of hydrogen in the presence of suitable bases in inert solvents to give the compounds of the formula I according to the invention.
- R4 is hydrogen
- suitable protecting groups and the methods of introduction and cleavage are known (See: Theodora W. Greene and Peter G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., New York, 1999).
- Suitable halogenating agents may be, for example, halogens, such as chlorine and bromine, N-bromosuccinimide, phosphorus pentoxide or phosphorus oxychloride.
- halogens such as chlorine and bromine, N-bromosuccinimide, phosphorus pentoxide or phosphorus oxychloride.
- the synthesis of compounds of the formula II has been described several times in the literature (see Houben Weyl E9b / 2, p. 331 ff).
- the radicals R 1 to R 3 can be prepared by methods known per se by alkylating appropriate precursors, the sequence being able to be varied. In some cases, however, they can also be introduced by selecting appropriate precursors in the preparation of the xanthine skeleton.
- the compounds of formula III are known or can be prepared by literature methods.
- the compounds of the formula I have favorable effects on the lipid and carbohydrate metabolism, in particular they lower the blood sugar level and are suitable for the treatment of type 2 diabetes, insulin resistance, dyslipidaemias and the metabolic syndrome / syndrome X. Furthermore, the compounds are suitable for the prophylaxis and treatment of arteriosclerotic phenomena.
- the compounds may be used alone or in combination with other blood sugar lowering agents.
- the compounds act as DPP-IV (dipeptidyl peptidase FV) inhibitors and are also useful in the treatment of disorders of sensation and other psychiatric indications such as depression, anxiety, anxiety disorders, schizophrenia, and the treatment of disorders associated with the circadian rhythm Weight reduction in mammals, for the treatment of immune disorders, and for the treatment of substance abuse.
- H-Ala-Pro-AFC (15 ⁇ M final concentration) in Tris / HCl (40 mM, pH 7.4), total volume 0.2 ml
- the reaction was carried out at room temperature for various periods of time (typically 10 minutes) and stopped at the end of the reaction by addition of 20 ⁇ l of ZnCl 2 (1 M).
- the conversion of H-Ala-Pro-AFC was determined fluorimetrically by measuring the emission at 535 nm after excitation at 405 nm.
- the added buffer volume was adjusted so that a total volume of the test mixture of 200 ⁇ l was maintained.
- IC50 values for inhibitors were determined by varying the inhibitor concentrations at the stated substrate concentration of 15 ⁇ M. Ki and Km values were determined by appropriate variation of substrate and inhibitor concentration as described (Dixon, M. and Webb, EC (1979) Enzymes, third edition, pp. 47-206, Academic Press).
- the Km, IC50 and Ki values were calculated using a commercially available software package (Leatherbarrow, RJ. (1992) GraFit Version 3.0, Erithacus Software Ltd. Staines, UK).
- Example 1 8- (2-Amino-2-methyl-propoxy) -3-methyl-7- (3-methyl-but-2-enyl) -1- (2-oxo-2-phenyl-ethyl) -
- Example 36 8- (3-Amino-2-methylpropoxy) -3
- This compound was prepared by chromatographic separation of the diastereomer mixture
- Example 36 on a chiral column (Chiralpak AD 10 ⁇ 40 cm, manufacturer Merck, eluent: methanol + 0.1% diethylamine, flow: 200 ml / min) as a faster eluting isomer.
- Phenacyl bromide and 25.4 g potash are placed in 400 ml of DMF and heated to 10 80 ° C internal temperature for 3 hours. The solution is cooled to about 50 ° C and slowly with 400ml
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Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002576561A CA2576561A1 (en) | 2004-08-14 | 2005-07-30 | Substituted 8-aminoalkoxi-xanthines, method for the production thereof and use thereof as medicaments |
MX2007001082A MX2007001082A (es) | 2004-08-14 | 2005-07-30 | 8 - aminoalcoxi - xantinas sustituidas, metodo para su produccion y su uso como medicamentos. |
AU2005274494A AU2005274494A1 (en) | 2004-08-14 | 2005-07-30 | Substituted 8-aminoalkoxi-xanthines, method for the production thereof and use thereof as medicaments |
BRPI0514310-1A BRPI0514310A (pt) | 2004-08-14 | 2005-07-30 | 8-aminoalcóxi-xantinas substituìdas, método para a produção das mesmas e seu uso como medicamentos |
JP2007525217A JP2008509893A (ja) | 2004-08-14 | 2005-07-30 | 置換8−アミノアルコキシ−キサンチン、それらの製造方法および医薬としてのそれらの使用 |
EP05770568A EP1778690B1 (de) | 2004-08-14 | 2005-07-30 | Substituierte 8-Aminoalkoxixanthine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
IL181012A IL181012A0 (en) | 2004-08-14 | 2007-01-28 | Substituted 8-aminoalkoxi-xanthines, method for the production thereof and use thereof as medicaments |
US11/674,261 US7879864B2 (en) | 2004-08-14 | 2007-02-13 | Substituted 8-aminoalkoxy-xanthine compounds and compositions useful in the treatment of hyperlipidemia and diabetes |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102004039507A DE102004039507A1 (de) | 2004-08-14 | 2004-08-14 | Substituierte 8-Aminoalkoxi-xanthine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
DE102004039507.1 | 2004-08-14 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US11/674,261 Continuation US7879864B2 (en) | 2004-08-14 | 2007-02-13 | Substituted 8-aminoalkoxy-xanthine compounds and compositions useful in the treatment of hyperlipidemia and diabetes |
Publications (1)
Publication Number | Publication Date |
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WO2006018117A1 true WO2006018117A1 (de) | 2006-02-23 |
Family
ID=35478703
Family Applications (1)
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PCT/EP2005/008283 WO2006018117A1 (de) | 2004-08-14 | 2005-07-30 | Substituierte 8-aminoalkoxi-xanthine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
Country Status (10)
Country | Link |
---|---|
US (1) | US7879864B2 (de) |
EP (1) | EP1778690B1 (de) |
JP (1) | JP2008509893A (de) |
AU (1) | AU2005274494A1 (de) |
BR (1) | BRPI0514310A (de) |
CA (1) | CA2576561A1 (de) |
DE (1) | DE102004039507A1 (de) |
IL (1) | IL181012A0 (de) |
MX (1) | MX2007001082A (de) |
WO (1) | WO2006018117A1 (de) |
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WO2009021740A2 (de) | 2007-08-15 | 2009-02-19 | Sanofis-Aventis | Substituierte tetrahydronaphthaline, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
WO2010003624A2 (en) | 2008-07-09 | 2010-01-14 | Sanofi-Aventis | Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof |
WO2010068601A1 (en) | 2008-12-08 | 2010-06-17 | Sanofi-Aventis | A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof |
US7875633B2 (en) | 2005-08-24 | 2011-01-25 | Banyu Pharmaceutical Co., Ltd. | Phenylpyridone derivative |
WO2011023754A1 (en) | 2009-08-26 | 2011-03-03 | Sanofi-Aventis | Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use |
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WO2011157827A1 (de) | 2010-06-18 | 2011-12-22 | Sanofi | Azolopyridin-3-on-derivate als inhibitoren von lipasen und phospholipasen |
WO2011161030A1 (de) | 2010-06-21 | 2011-12-29 | Sanofi | Heterocyclisch substituierte methoxyphenylderivate mit oxogruppe, verfahren zu ihrer herstellung und ihre verwendung als gpr40 rezeptor modulatoren |
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WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
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WO2016151018A1 (en) | 2015-03-24 | 2016-09-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method and pharmaceutical composition for use in the treatment of diabetes |
CN112533607A (zh) * | 2018-05-25 | 2021-03-19 | 普利缪尼治疗学股份有限公司 | Tlr7激动剂 |
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DE102004037554A1 (de) * | 2004-08-03 | 2006-03-16 | Sanofi-Aventis Deutschland Gmbh | Substituierte 8-Aminoalkylthio-xanthine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
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WO2016151018A1 (en) | 2015-03-24 | 2016-09-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method and pharmaceutical composition for use in the treatment of diabetes |
CN112533607A (zh) * | 2018-05-25 | 2021-03-19 | 普利缪尼治疗学股份有限公司 | Tlr7激动剂 |
Also Published As
Publication number | Publication date |
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JP2008509893A (ja) | 2008-04-03 |
MX2007001082A (es) | 2007-04-19 |
EP1778690A1 (de) | 2007-05-02 |
US7879864B2 (en) | 2011-02-01 |
US20070299090A1 (en) | 2007-12-27 |
CA2576561A1 (en) | 2006-02-23 |
DE102004039507A1 (de) | 2006-03-02 |
BRPI0514310A (pt) | 2008-06-10 |
IL181012A0 (en) | 2007-07-04 |
EP1778690B1 (de) | 2012-08-22 |
AU2005274494A1 (en) | 2006-02-23 |
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