BRPI0512680A - derivados de oxopiperidina, sua preparação e sua aplicação em terapêutica - Google Patents

derivados de oxopiperidina, sua preparação e sua aplicação em terapêutica

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Publication number
BRPI0512680A
BRPI0512680A BRPI0512680-0A BRPI0512680A BRPI0512680A BR PI0512680 A BRPI0512680 A BR PI0512680A BR PI0512680 A BRPI0512680 A BR PI0512680A BR PI0512680 A BRPI0512680 A BR PI0512680A
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Brazil
Prior art keywords
preparation
alkyl
application
nrr
cycloalkyl
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Application number
BRPI0512680-0A
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English (en)
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Alain Braun
Giller Courtemanche
Oliver Crespin
Eykmar Fett
Cecile Pascal
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Safoni Aventis
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Application filed by Safoni Aventis filed Critical Safoni Aventis
Publication of BRPI0512680A publication Critical patent/BRPI0512680A/pt

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/12Heterocyclic 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 chain containing hetero atoms as chain links
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10Drugs for genital or sexual disorders; Contraceptives for impotence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32Alcohol-abuse
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D295/00Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/108Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/06Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/14Heterocyclic 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 three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D451/00Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D453/00Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Addiction (AREA)
  • Reproductive Health (AREA)
  • Psychiatry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Emergency Medicine (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Gynecology & Obstetrics (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

DERIVADOS DE OXOPIPERIDINA, SUA PREPARAçãO E SUA APLICAçãO EM TERAPêUTICA. A presente invenção refere-se aos derivados de oxopiperidina de fórmula geral (<124>): na qual: n é igual 1, R~ a~, R~ a~,, R~ b~, e R~ b~ representam átomos de hidrogênio ou grupos alquilas ou cicloalquilas,ou R~ b~ e R~ b~, formam juntos uma ponte carbonada, R~ 1~ representa um grupo alquila ou cicloalquila, R~ 2~ representa um grupo heteroarila, R~ 3~ representa 1 a 3 grupos, escolhidos dentre os átomos de halogênio e os grupos alquilas, cicloalquilas, -OR, -NRR<39>, -CO-NRR<39>, -NR-COR<39>, -NR-CO-NRR<39>, -NR-COOR<39>, -NO~ 2~, -CN e -COOR, R~ 5~ representa um átomo de hidrogênio ou um grupo alquila, R~ 4~ é escolhido dentre os grupos de fórmulas (a), (b) e (c), nas quais p = 0,1, 2 ou 3, m = 0, 1 ou 2, e X representa uma cadeia -C(R~ 6~)(R~ 7~)-ou -N(R~ 10~)-: Processo de preparação e aplicação em terapêutica.
BRPI0512680-0A 2004-07-29 2005-07-20 derivados de oxopiperidina, sua preparação e sua aplicação em terapêutica BRPI0512680A (pt)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0408369A FR2873690B1 (fr) 2004-07-29 2004-07-29 Derives d'oxopiperidine, leur preparation et leur application en therapeutique
PCT/FR2005/001854 WO2006021655A2 (fr) 2004-07-29 2005-07-20 Dérivés doxopiperidine, leur préparation et leur application en thérapeutique

Publications (1)

Publication Number Publication Date
BRPI0512680A true BRPI0512680A (pt) 2008-04-01

Family

ID=34947722

Family Applications (1)

Application Number Title Priority Date Filing Date
BRPI0512680-0A BRPI0512680A (pt) 2004-07-29 2005-07-20 derivados de oxopiperidina, sua preparação e sua aplicação em terapêutica

Country Status (25)

Country Link
US (1) US20070149562A1 (pt)
EP (1) EP1773796B1 (pt)
JP (1) JP4871866B2 (pt)
KR (1) KR20070047802A (pt)
CN (1) CN101010309A (pt)
AR (1) AR054208A1 (pt)
AT (1) ATE459608T1 (pt)
AU (1) AU2005276353C1 (pt)
BR (1) BRPI0512680A (pt)
CA (1) CA2577177A1 (pt)
CY (1) CY1110124T1 (pt)
DE (1) DE602005019743D1 (pt)
DK (1) DK1773796T3 (pt)
ES (1) ES2341722T3 (pt)
FR (1) FR2873690B1 (pt)
IL (1) IL180770A (pt)
MX (1) MX2007001139A (pt)
PE (1) PE20060563A1 (pt)
PL (1) PL1773796T3 (pt)
PT (1) PT1773796E (pt)
RU (1) RU2376298C2 (pt)
SI (1) SI1773796T1 (pt)
TW (1) TW200609217A (pt)
UY (1) UY29036A1 (pt)
WO (1) WO2006021655A2 (pt)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2873691B1 (fr) * 2004-07-29 2006-10-06 Sanofi Synthelabo Derives d'amino-piperidine, leur preparation et leur application en therapeutique
RU2009108280A (ru) 2006-08-08 2010-09-20 Санофи-Авентис (Fr) Ариламиноарилалкилзамещенные имидазолидин-2,4-дионы, способы их получения, содержащие эти соединения лекарственные средства и их применение
EP2020405A1 (en) * 2007-07-30 2009-02-04 Santhera Pharmaceuticals (Schweiz) AG Substituted aryl or heteroarylpiperidine derivatives as melanocortin-4 receptor modulators
EP2025674A1 (de) 2007-08-15 2009-02-18 sanofi-aventis Substituierte Tetrahydronaphthaline, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
UY31968A (es) 2008-07-09 2010-01-29 Sanofi Aventis Nuevos derivados heterocíclicos, sus procesos para su preparación, y sus usos terapéuticos
US8871758B2 (en) 2011-03-08 2014-10-28 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
US8846666B2 (en) 2011-03-08 2014-09-30 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120052A1 (de) 2011-03-08 2012-09-13 Sanofi Mit carbozyklen oder heterozyklen substituierte oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
US8828995B2 (en) 2011-03-08 2014-09-09 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
US8809324B2 (en) 2011-03-08 2014-08-19 Sanofi Substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120057A1 (de) 2011-03-08 2012-09-13 Sanofi Neue substituierte phenyl-oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
WO2012120054A1 (de) 2011-03-08 2012-09-13 Sanofi Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
EP2683699B1 (de) 2011-03-08 2015-06-24 Sanofi Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
US8809325B2 (en) 2011-03-08 2014-08-19 Sanofi Benzyl-oxathiazine derivatives substituted with adamantane and noradamantane, medicaments containing said compounds and use thereof
WO2013134376A1 (en) * 2012-03-06 2013-09-12 Vanderbilt University Positive allosteric modulators for melanocortin receptors

Family Cites Families (12)

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US5968929A (en) * 1996-10-30 1999-10-19 Schering Corporation Piperazino derivatives as neurokinin antagonists
JP2003505435A (ja) * 1999-06-04 2003-02-12 メルク エンド カムパニー インコーポレーテッド メラノコルチン−4受容体ゴニストとしての置換ピペリジン
AU4929601A (en) * 2000-03-23 2001-10-03 Merck & Co Inc Substituted piperidines as melanocortin receptor agonists
EP1320366A4 (en) * 2000-08-23 2005-04-06 Merck & Co Inc SUBSTITUTED PIPERIDINES AS AGONISTS OF MELANOCORTIN RECEPTORS
WO2002070511A1 (en) * 2001-03-02 2002-09-12 Bristol-Myers Squibb Company Compounds useful as modulators of melanocortin receptors and pharmaceutical compositions comprising same
JP4336196B2 (ja) * 2001-07-18 2009-09-30 メルク エンド カムパニー インコーポレーテッド メラノコルチン受容体作動薬としての架橋ピペリジン誘導体
US6977264B2 (en) * 2001-07-25 2005-12-20 Amgen Inc. Substituted piperidines and methods of use
US20040010010A1 (en) * 2002-04-30 2004-01-15 Ebetino Frank Hallock Melanocortin receptor ligands
US7049323B2 (en) * 2003-04-25 2006-05-23 Bristol-Myers Squibb Company Amidoheterocycles as modulators of the melanocortin-4 receptor
KR20050045927A (ko) * 2003-11-12 2005-05-17 주식회사 엘지생명과학 멜라노코틴 수용체의 항진제
FR2873693B1 (fr) * 2004-07-29 2006-09-15 Sanofi Synthelabo Derives d'amino-tropane, leur preparation et leur application en therapeutique
FR2873691B1 (fr) * 2004-07-29 2006-10-06 Sanofi Synthelabo Derives d'amino-piperidine, leur preparation et leur application en therapeutique

Also Published As

Publication number Publication date
ATE459608T1 (de) 2010-03-15
JP4871866B2 (ja) 2012-02-08
UY29036A1 (es) 2006-02-24
AR054208A1 (es) 2007-06-13
RU2376298C2 (ru) 2009-12-20
ES2341722T3 (es) 2010-06-25
AU2005276353C1 (en) 2012-03-29
CA2577177A1 (fr) 2006-03-02
AU2005276353B2 (en) 2011-12-01
JP2008508240A (ja) 2008-03-21
FR2873690B1 (fr) 2006-10-13
MX2007001139A (es) 2007-04-19
PE20060563A1 (es) 2006-07-12
PL1773796T3 (pl) 2010-08-31
KR20070047802A (ko) 2007-05-07
DE602005019743D1 (de) 2010-04-15
RU2007107374A (ru) 2008-09-10
AU2005276353A1 (en) 2006-03-02
TW200609217A (en) 2006-03-16
IL180770A (en) 2011-10-31
IL180770A0 (en) 2007-06-03
SI1773796T1 (sl) 2010-07-30
WO2006021655A8 (fr) 2007-05-24
CN101010309A (zh) 2007-08-01
CY1110124T1 (el) 2015-01-14
WO2006021655A2 (fr) 2006-03-02
WO2006021655A3 (fr) 2006-04-20
PT1773796E (pt) 2010-06-01
EP1773796B1 (fr) 2010-03-03
US20070149562A1 (en) 2007-06-28
EP1773796A2 (fr) 2007-04-18
DK1773796T3 (da) 2010-06-21
FR2873690A1 (fr) 2006-02-03

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