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AR045879A1 - USE OF AN NK3 RECEIVER ANTAGONIST TO PREPARE A PHARMACEUTICAL COMPOSITION - Google Patents

USE OF AN NK3 RECEIVER ANTAGONIST TO PREPARE A PHARMACEUTICAL COMPOSITION

Info

Publication number
AR045879A1
AR045879A1 ARP020101845A ARP020101845A AR045879A1 AR 045879 A1 AR045879 A1 AR 045879A1 AR P020101845 A ARP020101845 A AR P020101845A AR P020101845 A ARP020101845 A AR P020101845A AR 045879 A1 AR045879 A1 AR 045879A1
Authority
AR
Argentina
Prior art keywords
alkyl
group
ring
optionally substituted
pharmaceutically acceptable
Prior art date
Application number
ARP020101845A
Other languages
Spanish (es)
Original Assignee
Smithkline Beecham Plc
Smithkline Beecham Corp
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
Priority claimed from GB0112208A external-priority patent/GB0112208D0/en
Priority claimed from GB0129268A external-priority patent/GB0129268D0/en
Application filed by Smithkline Beecham Plc, Smithkline Beecham Corp filed Critical Smithkline Beecham Plc
Publication of AR045879A1 publication Critical patent/AR045879A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P1/10—Laxatives
    • 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
    • A61P1/12—Antidiarrhoeals
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Nutrition Science (AREA)
  • Neurology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Uso de un antagonista del receptor NK3 para preparar una composición farmacéutica de aplicación en un método para el tratamiento y/o la profilaxis de estados individualizados por una función intestinal alterada y/o dolor visceral en seres humanos o en mamíferos no humanos, método que comprende la administración de una cantidad efectiva, no tóxica y farmacéuticamente aceptable de dicho antagonista del receptor NK3, en el que la condición comprende una función intestinal alterada y/o dolor visceral se selecciona entre determinados estados del síndrome del intestino irritable, distensión abdominal funcional, estrenimiento funcional, diarrea funcional, otros estados intestinales y dolor abdominal funcional. El antagonista del receptor NK3 puede ser un compuesto de la fórmula (1) o de uno de sus solvatos farmacéuticamente aceptables, o de una de sus sales farmacéuticamente aceptables. Preferentemente dicho antagonista del receptor NK3 es seleccionado entre la lista constituida por óxido de [[(diclorofenil)(trime-toxibenzoil)morfolinil]etil]espiro [benzo(c)tiofenopiperidina], R113281, N10A, N5A1, SR-142801, SSR-146977, Cam-2425 y MDL-105212, o, según convenga, uno de sus derivados farmacéuticamente aceptables. Reivindicación 4: El uso según la reivindicación 1, caracterizado porque dicho antagonista del receptor NK3 es un compuesto de la fórmula (1) o uno de sus solvatos farmacéuticamente aceptables, o de una de sus sales farmacéuticamente aceptables, en la que: Ar es un fenilo opcionalmente sustituido, naftilo o un grupo cicloalcadienilo (C5-7), o un grupo heterocíclico opcionalmente sustituido, solo o fusionado con un anillo, que tiene carácter aromático, que contiene de 5 a 12 átomos en el anillo, y que comprende hasta un máximo de cuatro heteroátomos en el anillo o en cada uno de los anillos, seleccionados entre S, O, N; Res un alquilo (C1-8) lineal o ramificado, cicloalquilo (C3-7), cicloalquilalquilo (C4-7), fenilo o fenilalquilo (C1-6) opcionalmente sustituido, un anillo heteroaromático de5 miembros y opcionalmente sustituido, que comprende hasta 4 heteroátomos seleccionados entre O y N, hidroxialquilo (C1-6), aminoalquilo (C1-6), alquilaminoalquilo (C1-6), di-alquilaminoalquilo (C1-6), acilaminoalquilo (C1-6), alcoxialquilo (C1-6), alquil(C1-6)carbonilo, carboxi, alcoxi (C1-6)carbonilo, alcoxi (C1-6)carbonilalquilo (C1-6), aminocarbonilo, alquil(C1-6)aminocarbonilo, di-alquil(C1-6)aminocarbonilo, alquilo (C1-6)halogenado; o es un grupo -(CH2)p- cuando se cicla sobre Ar, en donde p es 2 o 3; R1 y R2 que pueden ser el mismo grupo o un grupo diferente, de manera independiente son H o un alquilo (C1-6) lineal o ramificado, o juntos forman un grupo -(CH2)n-, en el que n representa 3, 4 o 5; o R1 junto con R forma un grupo -(CH2)q-, en el que q es 2, 3, 4 o 5; R3 y R4, que pueden ser el mismo grupo o un grupo diferente, de manera independiente son H o un alquilo (C1-6) lineal o ramificado, alquenilo (C1-6), arilo, alcoxi (C1-6), hidroxi, halógeno, nitro, ciano, carboxi, carboxamido, sulfonamido, alcoxi (C1-6)carbonilo, trifluorometilo, aciloxi, ftalimido, amino, mono- y di-alquil (C1-6)amino, -O(CH2)r-NT, en el que r es 2, 3 o 4 y T es H o un alquilo (C1-6) o forma con el N adyacente un grupo como se muestra en las fórmulas (2), en el que V y V1 de manera independiente son H u O, y u es 0, 1 o 2; -O(CH2)s-OW en el que s es 2, 3 o 4 y W es H o alquilo (C1-6); hidroxialquilo, alquilamino, mono- o di- alquilaminoalquilo, acilamino, alquilsulfonilamino, aminoacilamino, mono- o di-alquilaminoacilamino; con hasta 4 sustituyentes R3 que están presentes en el núcleo de quinolina; o R4 es un grupo -(CH2)t- cuando se cicla sobre R5 como arilo, en el que t es 1, 2 o 3; R5 es un alquilo (C1-6) lineal o ramificado, cicloalquilo (C3-7), cicloalquilalquilo (C4-7), arilo opcionalmente sustituido, o un grupo heterocíclico opcionalmente sustituido, solo o fusionado a un anillo, que tiene carácter aromático, que contiene de 5 a 12 átomos en el anillo y que comprende hasta 4 heteroátomos en el anillo o en cada uno de los anillos, seleccionados entre S, O y N; X es O, S o N-C:::N.Use of an NK3 receptor antagonist to prepare a pharmaceutical composition for application in a method for the treatment and / or prophylaxis of states individualized by altered intestinal function and / or visceral pain in humans or in non-human mammals, a method comprising the administration of an effective, non-toxic and pharmaceutically acceptable amount of said NK3 receptor antagonist, wherein the condition comprises an altered intestinal function and / or visceral pain is selected from certain states of irritable bowel syndrome, functional abdominal distension, constipation functional, functional diarrhea, other intestinal states and functional abdominal pain. The NK3 receptor antagonist can be a compound of the formula (1) or one of its pharmaceutically acceptable solvates, or one of its pharmaceutically acceptable salts. Preferably said NK3 receptor antagonist is selected from the list consisting of [[(dichlorophenyl) (trime-toxibenzoyl) morpholinyl] ethyl] spiro [benzo (c) thiophenepiperidine] oxide, R113281, N10A, N5A1, SR-142801, SSR- 146977, Cam-2425 and MDL-105212, or, as appropriate, one of its pharmaceutically acceptable derivatives. Claim 4: The use according to claim 1, characterized in that said NK3 receptor antagonist is a compound of the formula (1) or a pharmaceutically acceptable solvate thereof, or of a pharmaceutically acceptable salt thereof, wherein: Ar is a optionally substituted phenyl, naphthyl or a cycloalcadienyl (C5-7) group, or an optionally substituted heterocyclic group, alone or fused with a ring, which has an aromatic character, containing 5 to 12 ring atoms, and comprising up to a maximum of four heteroatoms in the ring or in each of the rings, selected from S, O, N; Res is a linear or branched (C1-8) alkyl, (C3-7) cycloalkyl, (C4-7) cycloalkylalkyl, optionally substituted phenyl or (C1-6) alkyl, a 5-membered and optionally substituted heteroaromatic ring, comprising up to 4 heteroatoms selected from O and N, hydroxyalkyl (C1-6), aminoalkyl (C1-6), alkylaminoalkyl (C1-6), di-alkylaminoalkyl (C1-6), acylaminoalkyl (C1-6), alkoxyalkyl (C1-6) , (C1-6) alkylcarbonyl, carboxy, (C1-6) alkoxycarbonyl, (C1-6) alkoxycarbonyl (C1-6), aminocarbonyl, (C1-6) alkylcarbonyl, di- (C1-6) alkyl aminocarbonyl, halogenated (C1-6) alkyl; or is a group - (CH2) p- when cycling on Ar, where p is 2 or 3; R1 and R2 which can be the same group or a different group, independently are H or a linear or branched (C1-6) alkyl, or together form a group - (CH2) n-, in which n represents 3, 4 or 5; or R1 together with R forms a group - (CH2) q-, in which q is 2, 3, 4 or 5; R3 and R4, which may be the same or a different group, independently are H or a linear or branched (C1-6) alkyl, (C1-6) alkenyl, aryl, (C1-6) alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulfonamido, (C1-6) alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono- and di-(C1-6) alkyl, -O (CH2) r-NT, wherein r is 2, 3 or 4 and T is H or a (C1-6) alkyl or forms with the adjacent N a group as shown in formulas (2), in which V and V1 independently are H or O, and u is 0, 1 or 2; -O (CH2) s-OW in which s is 2, 3 or 4 and W is H or (C1-6) alkyl; hydroxyalkyl, alkylamino, mono- or di-alkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or di-alkylaminoacylamino; with up to 4 R3 substituents that are present in the quinoline core; or R4 is a group - (CH2) t- when cyclized on R5 as aryl, in which t is 1, 2 or 3; R5 is a linear or branched (C1-6) alkyl, (C3-7) cycloalkyl, (C4-7) cycloalkylalkyl, optionally substituted aryl, or an optionally substituted heterocyclic group, alone or fused to a ring, which has an aromatic character, containing from 5 to 12 atoms in the ring and comprising up to 4 heteroatoms in the ring or in each of the rings, selected from S, O and N; X is O, S or N-C ::: N.

ARP020101845A 2001-05-18 2002-05-17 USE OF AN NK3 RECEIVER ANTAGONIST TO PREPARE A PHARMACEUTICAL COMPOSITION AR045879A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0112208A GB0112208D0 (en) 2001-05-18 2001-05-18 New use
GB0129268A GB0129268D0 (en) 2001-12-06 2001-12-06 Novel use

Publications (1)

Publication Number Publication Date
AR045879A1 true AR045879A1 (en) 2005-11-16

Family

ID=26246093

Family Applications (1)

Application Number Title Priority Date Filing Date
ARP020101845A AR045879A1 (en) 2001-05-18 2002-05-17 USE OF AN NK3 RECEIVER ANTAGONIST TO PREPARE A PHARMACEUTICAL COMPOSITION

Country Status (19)

Country Link
EP (1) EP1387687A4 (en)
JP (1) JP2004534761A (en)
KR (1) KR20040016865A (en)
CN (1) CN1269483C (en)
AR (1) AR045879A1 (en)
AU (1) AU2002303811B2 (en)
BR (1) BR0209662A (en)
CA (1) CA2447063A1 (en)
CZ (1) CZ20033115A3 (en)
HU (1) HUP0400966A2 (en)
IL (1) IL158701A0 (en)
MX (1) MXPA03010509A (en)
MY (1) MY134211A (en)
NO (1) NO20035121D0 (en)
NZ (1) NZ529462A (en)
PE (1) PE20021067A1 (en)
PL (1) PL367308A1 (en)
TW (1) TWI243678B (en)
WO (1) WO2002094187A2 (en)

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ATE365174T1 (en) 2003-01-28 2007-07-15 Microbia Inc COMPOSITIONS FOR TREATING GASTROINTESTINAL DISORDERS
BRPI0508111A (en) * 2004-03-30 2007-07-17 Smithkline Beecham Corp spray dried pharmaceutical compositions
WO2005100997A2 (en) * 2004-04-16 2005-10-27 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with tachykinin receptor 3 (tacr3)
US20080255193A1 (en) * 2005-09-30 2008-10-16 Jeffrey Brum Pharmaceutical Composition
TW201018662A (en) 2005-12-12 2010-05-16 Astrazeneca Ab Alkylsulphonamide quinolines
CA2688161C (en) 2007-06-04 2020-10-20 Kunwar Shailubhai Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
ES2522968T3 (en) 2008-06-04 2014-11-19 Synergy Pharmaceuticals Inc. Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2010009319A2 (en) 2008-07-16 2010-01-21 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
WO2018129556A1 (en) 2017-01-09 2018-07-12 Ardelyx, Inc. Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
KR101683318B1 (en) 2008-12-31 2016-12-07 알데릭스, 인코포레이티드 Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
KR200452372Y1 (en) * 2010-05-14 2011-02-22 서일수 Communication line support device of construction lift
KR101034774B1 (en) * 2010-07-30 2011-05-17 (주)챔피온코리아 Lift device using wire rope
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
US10376481B2 (en) 2012-08-21 2019-08-13 Ardelyx, Inc. Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
WO2014029983A1 (en) 2012-08-21 2014-02-27 Ardelyx, Inc. Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
CA2905438A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
EP2968439A2 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
RU2675364C2 (en) 2013-04-12 2018-12-19 Арделикс, Инк Nhe3-binding compounds and methods for inhibiting phosphate transport
EP2986293A1 (en) 2013-04-19 2016-02-24 Astrazeneca AB A nk3 receptor antagonist compound (nk3ra) for use in a method for the treatment of polycystic ovary syndrome (pcos)
KR102272746B1 (en) 2013-06-05 2021-07-08 보슈 헬스 아일랜드 리미티드 Ultra-pure agonists of guanylate cyclase c, method of making and using same
CN118221656A (en) 2017-01-09 2024-06-21 阿德利克斯股份有限公司 Compounds useful for the treatment of gastrointestinal disorders
US11147884B2 (en) 2017-01-09 2021-10-19 Ardelyx, Inc. Inhibitors of NHE-mediated antiport

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FR2719311B1 (en) * 1994-03-18 1998-06-26 Sanofi Sa Compounds that are selective antagonists of the human NK3 receptor and their use as drugs and diagnostic tools.
US5434158A (en) * 1994-04-26 1995-07-18 Merck & Co., Inc. Spiro-substituted azacycles as neurokinin-3 antagonists
AR004735A1 (en) * 1995-11-24 1999-03-10 Smithkline Beecham Spa CHINOLEIN 4-AMIDO SUBSTITUTED, A PROCEDURE FOR ITS PREPARATION, A PHARMACEUTICAL COMPOSITION THAT CONTAINS THEM AND THE USE OF THE SAME FOR THE PREPARATION OF A MEDICINAL PRODUCT.
JP2002500645A (en) * 1997-05-23 2002-01-08 スミスクライン・ビーチャム・ソシエタ・ペル・アチオニ Quinoline-4-carboxamide derivatives as NK-2 and NK-3 receptor antagonists
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Also Published As

Publication number Publication date
AU2002303811B2 (en) 2005-07-07
CN1269483C (en) 2006-08-16
NO20035121L (en) 2003-11-17
CZ20033115A3 (en) 2004-09-15
JP2004534761A (en) 2004-11-18
KR20040016865A (en) 2004-02-25
BR0209662A (en) 2004-04-20
PE20021067A1 (en) 2003-02-02
TWI243678B (en) 2005-11-21
CA2447063A1 (en) 2002-11-28
EP1387687A4 (en) 2006-07-05
CN1509175A (en) 2004-06-30
NZ529462A (en) 2005-07-29
NO20035121D0 (en) 2003-11-17
WO2002094187A3 (en) 2003-05-30
IL158701A0 (en) 2004-05-12
MXPA03010509A (en) 2004-03-02
HUP0400966A2 (en) 2004-08-30
PL367308A1 (en) 2005-02-21
EP1387687A2 (en) 2004-02-11
WO2002094187A2 (en) 2002-11-28
MY134211A (en) 2007-11-30

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