WO1998004289A2 - Composition pharmaceutique contenant un antagoniste 5ht2c et un antagoniste d¿2? - Google Patents

Composition pharmaceutique contenant un antagoniste 5ht2c et un antagoniste d¿2? Download PDF

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Publication number
WO1998004289A2
WO1998004289A2 PCT/EP1997/004159 EP9704159W WO9804289A2 WO 1998004289 A2 WO1998004289 A2 WO 1998004289A2 EP 9704159 W EP9704159 W EP 9704159W WO 9804289 A2 WO9804289 A2 WO 9804289A2
Authority
WO
WIPO (PCT)
Prior art keywords
antagonist
compound
pharmaceutically acceptable
5ht2c
pharmaceutical composition
Prior art date
Application number
PCT/EP1997/004159
Other languages
English (en)
Other versions
WO1998004289A3 (fr
Inventor
Thomas Paul Blackburn
Original Assignee
Smithkline Beecham Plc
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 to EP97918947A priority Critical patent/EP0936924A2/fr
Priority to IL12821997A priority patent/IL128219A0/xx
Priority to AU42972/97A priority patent/AU725817B2/en
Priority to BR9710568A priority patent/BR9710568A/pt
Priority to NZ333813A priority patent/NZ333813A/xx
Priority to CA002261813A priority patent/CA2261813A1/fr
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP10508522A priority patent/JP2000516924A/ja
Priority to PL97331426A priority patent/PL331426A1/xx
Priority to HU9903619A priority patent/HUP9903619A3/hu
Publication of WO1998004289A2 publication Critical patent/WO1998004289A2/fr
Publication of WO1998004289A3 publication Critical patent/WO1998004289A3/fr
Priority to NO990322A priority patent/NO990322L/no

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
    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to novel combinations of compounds, pharmaceutical compositions containing them, and their use in therapy.
  • WO 95/21844, WO 95/29177, WO 96/02537 and WO 96/23783 disclose heterocyclic derivatives which are described as possessing 5HT2 receptor antagonist activity. These compounds are said to be of use in the treatment of various CNS disorders such as depression. D2-li e antagonists such as haloperidol, raclopride and sulpiride are known in the art, for example see Seeman et al., Current Opinion in Neurology and Neurosurgery, (1993), 6, 602 - 608.
  • the present invention therefore provides a pharmaceutical composition for the treatment or prevention of CNS disorders which comprises:
  • salts having 5HT2C or D2 activity can usually be isolated in salt form and the invention extends to compositions in which the compounds are in salt form.
  • Preferred salts are pharmaceutically acceptable salts, for example acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p-toluenesulphonates.
  • the invention also extends to compositions in which the compounds are in stereoisomeric or tautomeric forms.
  • Preferred 5HT2C antagonists include those disclosed in WO 92/05170, in particular the compound N-(l -methyl- lH-indol-5-yl)-N'-(3-pyridyl)urea (SB-200646).
  • Another preferred compound is 5-methyl-l-(3-pyridylcarbamoyl)-2,3-dihydropyrrollo[2,3-f]indole (SB-206553) which is disclosed as Example 1 of WO 94/04533 and pharmaceutically acceptable salts thereof.
  • a particularly preferred 5HT2C antagonist is 5-methyl- 6-trifluoromethyl-l-[6-(2-methylpyridin-3-yloxy)pyridin-3-ylcarbamoyl]indoline (SB- 243213) (which may also be called 2,3-dihydro-5-methyl-N-f2-(2-methyl-3- pyridinyl)oxy]-5-pyridinyl]-6-trifluoromethyl)-lH-indole-l-carboxamide) which is described as Example 1 in PCT/EP 97/03156.
  • 5HT2C antagonists include those compounds disclosed in WO 93/18028, WO 94/04533, WO 94/18170, WO 94/22871, WO 95/21844, WO 95/29177, WO 96/02537, WO 96/23783.
  • Preferred D2 antagonists include haloperidol, raclopride, sulpiride, ziprasidone, olanzapine, sertindole and quetiapine and pharmaceutically acceptable salts thereof.
  • the compounds having 5HT2C and D2 antagonist activity can be administered together or individually for the treatment of CNS disorders, that is to say either concurrently or non-concurrently.
  • Concurrent administration includes co- administration of separate dosage forms of the two agents or administration as a single dosage unit.
  • Non-concurrently shall be taken to mean that the two agents are administered more than 24 hours apart.
  • kits comprising in separate dosage forms a compound having 5HT2C antagonist activity and a compound having D2 antagonist activity.
  • kits are of use in providing to patients when administration of separate doses of the two active ingredients is required.
  • kits can also be provided where sequential administration of the 5HT2C antagonist and D2 antagonist is required.
  • the invention also extends to pharmaceutical compositions comprising a compound having antagonist activity at both the 5HT2C and D2 receptors, that is to say a single compound having dual activity, and a pharmaceutically acceptable carrier for the treatment or prevention of CNS disorders such as schizophrenia.
  • the invention therefore provides a compound having antagonist activity at both the 5HT2C and D2 receptors for use in the treatment of CNS disorders such as schizophrenia.
  • compositions of the present invention are expected to be of use in the treatment of CNS disorders disclosed in the above mentioned patent applications such as schizophrenia, mood disorders, including depression, seasonal effective disorder and dysthymia; anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; and disorders of eating behaviours, including anorexia nervosa and bulimia nervosa.
  • Other CNS disorders include Parkinson's disease, dementia in Parkinson's disease, neuroleptic- induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders. Therefore in a further aspect the present invention provides a pharmaceutical composition which comprises a compound having 5HT2C antagonist activity, a compound having D2 antagonist activity, and a pharmaceutically acceptable carrier for use in therapy.
  • the invention provides a pharmaceutical composition which comprises a compound having 5HT2C antagonist activity, a compound having D2 antagonist activity; and a pharmaceutically acceptable carrier in the manufacture of a medicament for the treatment of the aforementioned disorders.
  • the invention provides a pharmaceutical composition which comprises a compound having 5HT2C antagonist activity, a compound having D2 antagonist activity; and a pharmaceutically acceptable carrier for use in the treatment or prophylaxis of depression.
  • a pharmaceutical composition which comprises a compound having 5HT2C antagonist activity, a compound having D2 antagonist activity; and a pharmaceutically acceptable carrier for use in the treatment or prophylaxis of depression.
  • compositions of the invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Compositions of the invention can also be administered in combination with other medicaments, for example conventional antidepressants or anxiolytics.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • the dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
  • This compound can be prepared according to the procedure given in WO 92/05170.
  • This compound can be prepared according to the procedure given in Example 1 of WO 94/04533.
  • the hydrochloride can be prepared by treating a solution of the free base in methanol or propanol with concentrated hydrochloric acid.
  • Activity is assessed by the reversal of haloperidol-induced catalepsy in the rat (bar method).
  • a metal bar 10cm high x 10mm diameter is suspended between two upright posts, and the bar is divided into compartments with card or perspex partitions.
  • Groups of rats are dosed intraperitoneally with a range of doses of the test compound or vehicle.
  • the rats are positioned so that their hind legs contact the ground and their forelegs are draped over the horizontal bar.
  • the measure of catalepsy is taken as the time taken for the rat to remove the front paws from the bar, with a maximum measurement of 120 seconds and the test is repeated at 30, 60 and 90 minutes.
  • catalepsy rats are administered vehicle or haloperidol (3umol/kg ip) and tested for catalepsy at 30 and 60 minutes in the standard manner; the rats are then injected with a range of doses of the test compound and are tested for catalepsy 30 minutes later.
  • SB-228357 significantly reversed haloperidol-induced catalepsy at doses of 0.32, 3.2 and 10 mg/kg po.
  • SB-243213 significantly reversed haloperidol-induced catalepsy.
  • the 5HT2B antagonist, SB-215505 0.1-3.2 mg/kg po
  • the 5HT2A antagonist, MDL- 100907 did not reverse haloperidol-induced catalepsy.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Neurology (AREA)
  • Organic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention a trait à des combinaisons de composés possédant une activité antagoniste 5HT2C et D2, à des composés possédant une activité sur ces deux récepteurs, à des compositions pharmaceutiques contenant lesdits composés, et à leur utilisation dans le traitement de la schizophrénie.
PCT/EP1997/004159 1996-07-26 1997-07-22 Composition pharmaceutique contenant un antagoniste 5ht2c et un antagoniste d¿2? WO1998004289A2 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
IL12821997A IL128219A0 (en) 1996-07-26 1997-07-22 Pharmaceutical composition containing a 5ht2c antagonist and a d2 antagonist
AU42972/97A AU725817B2 (en) 1996-07-26 1997-07-22 Pharmaceutical composition containing a 5HT2c antagonist and a D2 antagonist
BR9710568A BR9710568A (pt) 1996-07-26 1997-07-22 Composi- o farmac-utica contendo um antagonista 5Hht2c e um antagonista d2
NZ333813A NZ333813A (en) 1996-07-26 1997-07-22 Pharmaceutical composition containing a 5HT2C antagonist and a D2 antagonist
CA002261813A CA2261813A1 (fr) 1996-07-26 1997-07-22 Composition pharmaceutique contenant un antagoniste 5ht2c et un antagoniste d2
EP97918947A EP0936924A2 (fr) 1996-07-26 1997-07-22 Composition pharmaceutique contenant un antagoniste 5ht 2c? et un antagoniste d 2?
JP10508522A JP2000516924A (ja) 1996-07-26 1997-07-22 ５ｈｔ▲下２ｃ▼アンタゴニストおよびｄ▲下２▼アンタゴニストを含む医薬組成物
PL97331426A PL331426A1 (en) 1996-07-26 1997-07-22 Pharmaceutic composition containing the 5ht2c antagonist and the d2 antagonist
HU9903619A HUP9903619A3 (en) 1996-07-26 1997-07-22 Pharmaceutical composition containing a 5ht2c antagonist and a d2 antagonist
NO990322A NO990322L (no) 1996-07-26 1999-01-25 Farmas°ytisk blanding inneholdende en 5HT2c-antagonist og en D2-antagonist

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9615767.2A GB9615767D0 (en) 1996-07-26 1996-07-26 Novel treatment
GB9615767.2 1996-07-26

Publications (2)

Publication Number Publication Date
WO1998004289A2 true WO1998004289A2 (fr) 1998-02-05
WO1998004289A3 WO1998004289A3 (fr) 1998-03-19

Family

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Family Applications (1)

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PCT/EP1997/004159 WO1998004289A2 (fr) 1996-07-26 1997-07-22 Composition pharmaceutique contenant un antagoniste 5ht2c et un antagoniste d¿2?

Country Status (19)

Country Link
EP (1) EP0936924A2 (fr)
JP (1) JP2000516924A (fr)
KR (1) KR20000029564A (fr)
CN (1) CN1230894A (fr)
AR (1) AR008083A1 (fr)
AU (1) AU725817B2 (fr)
BR (1) BR9710568A (fr)
CA (1) CA2261813A1 (fr)
CO (1) CO5031292A1 (fr)
CZ (1) CZ23799A3 (fr)
GB (1) GB9615767D0 (fr)
HU (1) HUP9903619A3 (fr)
IL (1) IL128219A0 (fr)
NO (1) NO990322L (fr)
NZ (1) NZ333813A (fr)
PL (1) PL331426A1 (fr)
TR (1) TR199900140T2 (fr)
WO (1) WO1998004289A2 (fr)
ZA (1) ZA976593B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6121259A (en) * 1998-11-23 2000-09-19 Sepracor Inc. Olanzapine-N-oxide compositions and methods
WO2000054764A2 (fr) * 1999-03-18 2000-09-21 Children's Hospital Research Foundation Traitement de la boulimie et de troubles de l'alimentation associes par administration d'antipsychotiques atypiques
WO2000071106A2 (fr) * 1999-05-19 2000-11-30 Astrazeneca Ab Methode de traitement
US6174882B1 (en) 1998-11-23 2001-01-16 Sepracor Inc. 2-hydroxymethylolanzapine compositions and methods
US6348455B1 (en) 1998-11-23 2002-02-19 Sepracor Inc. Desmetylolanzapine compositions and methods
US6369060B1 (en) * 1996-06-20 2002-04-09 Smithkline Beecham P.L.C. Indoline derivatives useful as 5-HT-2C receptor antagonists
WO2005013969A1 (fr) * 2003-07-15 2005-02-17 Janssen Pharmaceutica N.V. Agent antipsychotique a proprietes favorisant la socialisation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996029316A1 (fr) * 1995-03-19 1996-09-26 Wikstroem Haakan Esters de sulfone constituant de nouveaux analogues d'iso-clozapine et structures apparentees: neuroleptiques atypiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996029316A1 (fr) * 1995-03-19 1996-09-26 Wikstroem Haakan Esters de sulfone constituant de nouveaux analogues d'iso-clozapine et structures apparentees: neuroleptiques atypiques

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
A.M.J.MONTGOMERY ET AL.: "Potentiation of the effects of raclopride on sucrose consumption by the 5-HT2 antagonist ritanserin" PSYCHOPHARMACOLOGY, vol. 123, no. 1, 1996, pages 98-102, XP002051726 *
ARIEL Y. DEUTCH: "Mechanism of action of atypical antipsychotic drugs" SCHIZOPHREN. RES., vol. 4, no. 2, 1991, pages 121-156, XP002051731 *
D.S.BALDWIN ET AL.: "First clinical experience with olanzapine (LY 170053): results of an open-label safety and dose-ranging study in patients with schizophrenia" INT.CLIN.PSYCHOPHARMACOL., vol. 10, no. 4, 1995, pages 239-244, XP002051729 *
E.MEIER ET AL.: "The atypical neuroleptic, sertindole, is a 5-HT2C receptor antagonist" SOCIETY FOR NEUROSCIENCE ABSTRACTS, vol. 20, no. 1-2, 1994, page 1543 XP002051725 *
FRANK P. BYMASTER ET AL.: "Radioreceptor binding profile of the atypical antipsychotic olanzapine" NEUROPSYCHOPHARMACOLOGY, vol. 14, no. 2, February 1996, pages 87-96, XP002051728 *
HERBERT Y. MELTZER: "An overview of the mechanism of action of clozapine" J.CLIN.PSYCHIATRY, vol. 55, no. 9 suppl. B, 1994, pages 47-52, XP002051727 *
T.F.SEEGER ET AL.: "Ziprasidone (CP-88,059): A new antipsychotic with combined dopamine and serotonin receptor antagonist activity" J.PHARMACOL.EXP.THER., vol. 275, no. 1, 1995, pages 101-113, XP002051730 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6369060B1 (en) * 1996-06-20 2002-04-09 Smithkline Beecham P.L.C. Indoline derivatives useful as 5-HT-2C receptor antagonists
US6121259A (en) * 1998-11-23 2000-09-19 Sepracor Inc. Olanzapine-N-oxide compositions and methods
US6174882B1 (en) 1998-11-23 2001-01-16 Sepracor Inc. 2-hydroxymethylolanzapine compositions and methods
US6346528B1 (en) 1998-11-23 2002-02-12 Sepracor Inc. 2-Hydroxymethylolanzapine compositions and methods
US6348455B1 (en) 1998-11-23 2002-02-19 Sepracor Inc. Desmetylolanzapine compositions and methods
US6468997B2 (en) 1998-11-23 2002-10-22 Sepracor Inc. Desmethylolanzapine compositions and methods
WO2000054764A2 (fr) * 1999-03-18 2000-09-21 Children's Hospital Research Foundation Traitement de la boulimie et de troubles de l'alimentation associes par administration d'antipsychotiques atypiques
WO2000054764A3 (fr) * 1999-03-18 2001-02-01 Children S Hospital Res Founda Traitement de la boulimie et de troubles de l'alimentation associes par administration d'antipsychotiques atypiques
US6395727B1 (en) 1999-03-18 2002-05-28 The Cincinnati Children's Hospital Research Foundation Method of treating Bulimia Nervosa and related eating disorders by administration of atypical antipsychotic medications
WO2000071106A2 (fr) * 1999-05-19 2000-11-30 Astrazeneca Ab Methode de traitement
WO2000071106A3 (fr) * 1999-05-19 2002-05-10 Astrazeneca Ab Methode de traitement
WO2005013969A1 (fr) * 2003-07-15 2005-02-17 Janssen Pharmaceutica N.V. Agent antipsychotique a proprietes favorisant la socialisation

Also Published As

Publication number Publication date
WO1998004289A3 (fr) 1998-03-19
IL128219A0 (en) 1999-11-30
NO990322L (no) 1999-03-24
CO5031292A1 (es) 2001-04-27
CZ23799A3 (cs) 1999-06-16
ZA976593B (en) 1999-01-25
AU725817B2 (en) 2000-10-19
AU4297297A (en) 1998-02-20
GB9615767D0 (en) 1996-09-04
KR20000029564A (ko) 2000-05-25
NZ333813A (en) 2000-07-28
HUP9903619A3 (en) 2001-03-28
HUP9903619A2 (hu) 2000-10-28
CA2261813A1 (fr) 1998-02-05
PL331426A1 (en) 1999-07-19
EP0936924A2 (fr) 1999-08-25
CN1230894A (zh) 1999-10-06
NO990322D0 (no) 1999-01-25
AR008083A1 (es) 1999-12-09
BR9710568A (pt) 1999-08-17
JP2000516924A (ja) 2000-12-19
TR199900140T2 (xx) 1999-03-22

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