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AR059887A1 - Compuestos pirazolicos heterobiciclicos, composiciones farmaceuticas que los contienen, y usos en trastornos hiperproliferativos, tales como cancer - Google Patents

Compuestos pirazolicos heterobiciclicos, composiciones farmaceuticas que los contienen, y usos en trastornos hiperproliferativos, tales como cancer

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Publication number
AR059887A1
AR059887A1 ARP070100948A ARP070100948A AR059887A1 AR 059887 A1 AR059887 A1 AR 059887A1 AR P070100948 A ARP070100948 A AR P070100948A AR P070100948 A ARP070100948 A AR P070100948A AR 059887 A1 AR059887 A1 AR 059887A1
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AR
Argentina
Prior art keywords
alkyl
cr14r15
aryl
heteroaryl
nr10r11
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Application number
ARP070100948A
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English (en)
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Array Biopharma Inc
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Publication of AR059887A1 publication Critical patent/AR059887A1/es

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Endocrinology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pulmonology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Virology (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Transplantation (AREA)

Abstract

Reivindicacion 1: Un compuesto seleccionado de las Formulas (1a) y (1b): y sus sales aceptables para uso farmacéutico, donde: X es O, S o NR10; Z2 y Z3 se seleccionan independientemente de CR4 y N, donde cero o uno de Z2 y z3 es N, R1 es H, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, C(=O)NR10R11 o -(CR14R15)tNR10R11, o R1 es carbociclilo C3-12, heterociclilo C2-20, arilo C6-20 o heteroarilo C1-20, donde dicho alquilo, alquenilo, alquinilo, carbociclilo, heterociclilo, arilo y heteroarilo están opcionalmente sustituidos con uno más grupos independientemente seleccionados entre F, Cl, Br, I, CN, CF3, oxo, -OR10, SR10, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -(CR14R15)n-NR10R11, -NR10C(=Y)R13, -NR10C(=Y)OR11, -NR12C(=Y)NR10R11, - NR12SO2R10, -OC(=Y)R10, -OC(=Y)OR10, -OC(=Y)NR10R11, -OS(O)2(OR10), -OP(=Y)(OR10)(OR11), -OP(OR10)(OR11), -S(O)R10, -S(O)2R10, -S(O)2R10R11, -S(O)(OR10), -S(O)2(OR10), -SC(=Y)R10, -SC(=Y)OR10, -SC(=Y)NR10R11, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, cicloalquilo C3-12, heterociclilo C2-20, arilo C6-20, heteroarilo C1-20, -(CR14R15)-NR12C(=O)(CR14R15)NR10R11 y (CR14R15)tNR10R11, o R1 es NRxRY; R2 es H, CF3, CN, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -C(=O)NR12(CR14R15)tNR10R11, -SR10, - S(O)R10, -S(O)2R10, S(O)2NR10R11, -SC(=Y)R10, -SC(=Y)OR10, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, carbociclilo C3-12, heterociclilo C2-20, C6-20 arilo, o heteroarilo C1-20, donde dicho alquilo, alquenilo, alquinilo, carbociclilo, heterociclilo, arilo, y heteroariloestán opcionalmente sustituidos con uno o más grupos independientemente seleccionados de F, Cl, Br, I, (CH2)nOR10, (CH2)nNR10R11, heteroarilo y heterociclilo; R3 es carbociclilo C3-12, heterociclilo C2-20, arilo C6- 20 o heteroarilo, donde dicho carbociclilo, heterociclilo, arilo y heteroarilo están opcionalmente sustituidos con uno o más grupos independientemente seleccionados de F, Cl, Br, I, CN, CF3, OR10, SR10, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, - NR10R11, -NR10C(=Y)R13, -NR10C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12C(=O)C(=O)R10R11, -NR12C(=O)C(=O)Ora, -NR12SO2R10, -NR12C(=Y1)(CR14R15)nC(=Y2)NR10R11, -NR12C(=Y1)NR10C(=Y2)(CR14R15)nR11, -NR12C(=Y1)(CR14R15)nC(=Y2)-(CR14R15)mR10, -OC(=Y)R10, - OC(=Y)OR10, -OC(=Y)NR10R11, -OS(O)2(OR10), -OP(=Y)(OR10)(OR11), -OP(OR10)(OR11), -S(O)R10, -S(O)2R10, -S(O)2NR10R11, -S(O)(OR10), -S(O)2(OR10), -SC(=Y)R10, -SC(=Y)OR10, -SC(=Y)NR10R11, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, cicloalquilo C3- 12, heterociclilo C2-20, arilo C6-20 y heteroarilo C1-20, donde dicho alquilo, alquenilo, alquinilo, cicloalquilo, heterociclilo, arilo y heteroarilo están opcionalmente sustituidos con uno o más grupos independientemente seleccionados de F, Cl, Br, I, OH, alquilo C1-12, NR10R11, y (CR14R15)n-arilo; R4 es H, F, Cl, Br, CF3, CN, -C(=Y )OR10, -C(=Y)NR10r11, -NR10R11, NR10C(=Y)R11, NR10C(=Y)OR11, NR12C(=Y)NR10R11, NR12SO2NR10R11, -OR10, -OC(=Y)R10, -OC(=Y)OR10, -OC(=Y)NR10R11, - C(=O)NR12(CR14R15)tNR10R11, -OP(=Y)(OR10)(OR11), -OP(OR10)(OR11), -SR10, -S(O)R10, -S(O)2R10, -S(O)2NR10R11, -SC(=Y)R10, -SC(=Y)OR10, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, carbociclilo C3-12, heterociclilo C2-20, arilo C6-20 o heteroarilo C1-20; R10, R11 y R12 son independientemente H, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, carbociclilo C3-12, heterocicliclo (CR14R15)nC2-20, arilo (CR14R15)nC6-20, o heteroarilo C1-20, donde dicho alquilo, alquenilo, alquinilo, carbociclilo, heterociclilo, arilo, y heteroarilo están opcionalmente sustituidos con uno o más grupos independientemente seleccionados de F, Cl, Br I, SO2Rc, CN, Ora, NRaRb, C(=O)NRaRb, CRaC(=O)Rb, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, carbociclilo C3- 12, arilo C6-20 y heteroarilo C1-20, o R10 y R11 junto con el nitrogeno al cual están unidos opcionalmente forman un anillo heterocíclico C3-20 saturado, parcialmente insaturado o completamente insaturado que contiene uno o más átomos anulares adicionales seleccionados entre N, O o S, donde dicho anillo heterocíclico esta opcionalmente sustituido con uno o más grupos seleccionados independientemente entre oxo, (CH2)nORa, NRaRb, CF3, F, Cl, Br, I, SO2Ra, C(=O)Ra, NR10C(=Y)R11, C(=Y)NR10R11, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, cicloalquilo C3-12, heterocicliclo C2-20 y arilo C6-20 y heteroarilo C1-20, o R10 y r12 junto con los átomos a los cuales están unidos forman un anillo heterocíclico C3-20 sustituido con oxo opcionalmente fusionado con un anillo bencénico; R13 es H, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, (CR14R15)n-cicloalquilo, (CR14R15)n-heterociclilo, (CR14R15)n-arilo, (CR14R15)n-heteroarilo, (CR14R15)n-O-(CR14R15)m-arilo, (CR14R15)n-O- (CR14R15)m-arilo, (CR14R15)n-OR10, (CR14R15)n-NR10R11, (CR14R15)n-NR10C(=O)R11, o (CR14R15)n-NR10(SO2Me)-R11, donde dichas porciones alquilo, alquenilo, alquinilo, cicloalquilo, heterocicloalquilo, y heteroarilo están opcionalmente sustituidas con uno o más grupos independientemente seleccionados de F, Cl, Br, I, oxo, SO2Rc, CN, ORa, C(=O)Ra, C(=O)ORa, NRaRb, NRaC(=O)Rb, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, cicloalquilo C3-12, heterociclilo C2-20 y arilo C6-20 y heteroarilo C1-20, cada R14 y R15 es independientemente H, alquilo C1-12 o (CH2)t-arilo, o R14 y R15 junto con los átomos a los cuales están unidos forman un anillo carbocíclico C3-12 saturado o parcialmente saturado, o R10 y R15 junto con los átomos a los cuales están unidos forman un anillo heterocíclico monocíclico o bicíclico saturado o parcialmente insaturado sustituido con oxo también opcionalmente sustituido con uno más grupos independientemente seleccionados entre F, Cl, Br, I, ORa, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, cicloalquilo C3-12, heterociclilo C2-20 y arilo C6-20 y heteroarilo C1-20, donde dicho alquilo y arilo están opcionalmente sustituidos con uno o más grupos independientemente seleccionados de F, Cl, Br, y I, o R14 es cero y R10 y R15 junto con los átomos a los cuales están unidos forman un anillo heteroarilo C1-20 que tiene uno o más heteroátomos; Ra y Rb son independientemente H, alquilo C1-12, alquenilo C2-8, alquinilo C2-8, carbociclilo C3-12, heterociclilo C2-20, arilo C6-20 y heteroarilo C1-20, donde dicho alquilo, alquenilo, alquinilo, carbociclilo, heterociclilo, arilo, y heteroarilo están opcionalmente sustituidos con uno o más grupos alquilo C1-6; Rc es alquilo C1-12 o arilo C6-20, donde dicho alquilo y arilo estánm opcionalmente sustituidos con uno o más grupos independientemente seleccionados de F, Cl, Br, I, ORa y C(=O)NRaRb; Rx es H o alquilo C1-6; Ry es (i) (alquilo C1-6)NRjRk donde Fj y Rk son independientemente H o alquilo C1-6; (ii) cicloalquilo opcionalmente sustituidos con OH u -OC(=O)CF3; o (iii) un anillo heterocíclico de 5-6 miembros que tiene 1 a 2 heteroátomos del anillo independientemente seleccionados entre N y O y opcionalmente sustituidos con un grupo halogeno, alquilo C1-6, (alquilo C1-6)OH, (alquilo C1-6)O(alquilo C1-6), o fluoroalquilo C1-6; Y, Y1 e Y2 son independientemente O o S; t es 1, 2, 3, 4, 5 o 6; y n y m son independientemente 0, 1, 2, 3, 4, 5 o 6.
ARP070100948A 2006-03-07 2007-03-07 Compuestos pirazolicos heterobiciclicos, composiciones farmaceuticas que los contienen, y usos en trastornos hiperproliferativos, tales como cancer AR059887A1 (es)

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US77980506P 2006-03-07 2006-03-07
US87483206P 2006-12-14 2006-12-14

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AR059887A1 true AR059887A1 (es) 2008-05-07

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US (2) US7723330B2 (es)
EP (1) EP2001880A2 (es)
JP (1) JP2009529047A (es)
KR (1) KR20080110783A (es)
AR (1) AR059887A1 (es)
AU (1) AU2007224020A1 (es)
BR (1) BRPI0708615A2 (es)
CA (1) CA2645137A1 (es)
CL (1) CL2007000601A1 (es)
CO (1) CO6140061A2 (es)
CR (1) CR10338A (es)
EC (1) ECSP088791A (es)
IL (1) IL193587A0 (es)
MA (1) MA31339B1 (es)
MX (1) MX2008011220A (es)
NO (1) NO20084183L (es)
RU (1) RU2008139599A (es)
TW (1) TW200800996A (es)
WO (1) WO2007103308A2 (es)
ZA (1) ZA200807632B (es)

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CL2007000601A1 (es) 2008-01-25
BRPI0708615A2 (pt) 2011-06-07
KR20080110783A (ko) 2008-12-19
MX2008011220A (es) 2008-09-11
ZA200807632B (en) 2011-04-28
WO2007103308A3 (en) 2008-02-07
CA2645137A1 (en) 2007-09-13
US20070238726A1 (en) 2007-10-11
AU2007224020A1 (en) 2007-09-13
EP2001880A2 (en) 2008-12-17
JP2009529047A (ja) 2009-08-13
NO20084183L (no) 2008-11-24
CO6140061A2 (es) 2010-03-19
ECSP088791A (es) 2008-11-27
CR10338A (es) 2008-10-31
TW200800996A (en) 2008-01-01
IL193587A0 (en) 2009-08-03
WO2007103308A2 (en) 2007-09-13
US7723330B2 (en) 2010-05-25
US20100256356A1 (en) 2010-10-07

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