EP1320528A2 - Substituted phthalides as anti-convulsive drugs - Google Patents

Substituted phthalides as anti-convulsive drugs

Info

Publication number
EP1320528A2
EP1320528A2 EP01958282A EP01958282A EP1320528A2 EP 1320528 A2 EP1320528 A2 EP 1320528A2 EP 01958282 A EP01958282 A EP 01958282A EP 01958282 A EP01958282 A EP 01958282A EP 1320528 A2 EP1320528 A2 EP 1320528A2
Authority
EP
European Patent Office
Prior art keywords
formula
compound
compounds
defined hereinbefore
group
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP01958282A
Other languages
German (de)
English (en)
French (fr)
Inventor
Zongru Guo
Fengming Chu
Juntian Zhang
Guangzhong Yang
Bailing Xu
Xinyi Niu
Zhihong Ren
Pierre Lestage
Pierre Renard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute of Materia Medica of CAMS
Laboratoires Servier SAS
Original Assignee
Institute of Materia Medica of CAMS
Laboratoires Servier SAS
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
Application filed by Institute of Materia Medica of CAMS, Laboratoires Servier SAS filed Critical Institute of Materia Medica of CAMS
Publication of EP1320528A2 publication Critical patent/EP1320528A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to new substituted phthalides, to a process for their preparation and to pharmaceutical compositions containing them.
  • Epilepsy is a collective term used to describe a group of chronic convulsive disorders having in common the occurrence of brief episodes (seizures) associated with loss or disturbance of consciousness.
  • anti-epilepsy drugs available in clinical applications, such as Phenobarbital, Phenytoin, Zolenzepine, Ethosuximide, Paramethadione, Valproic acid. Although these medicines are able to protect patients from convulsion of various epilepsies to different extents, adverse effects and tolerance usually prevent long-term therapy. New compounds with novel structural features and with new mechanisms of action are needed in order to improve the therapeutic effect and eliminate or reduce the adverse response.
  • the compounds of the present invention are new, devoid of any toxicity and exhibit interesting pharmacological properties as anti-convulsants. Furthermore, they are potent calcium and sodium channel blockers conferring on them neuroprotective and cognition- enhancing properties.
  • R 1 represents a linear or branched (C 1 -C 12 )alkyl group or a ureido group
  • R 2 represents a hydrogen atom or a linear or branched (C 1 -C 12 )alkyl group
  • R 3 represents a group CN, NO 2 , NR a R' a , NR a SO 2 R' a , NR a CZR 5 or CZNR a R' a wherein Z represents an oxygen or sulphur atom and R 5 represents a group OR a , R a or NR a R' a
  • R a and R' a which may be the same or different, represent a hydrogen atom or a linear or branched (C ⁇ -C 6 )alkyl group, a (C 3 -C 8 )cycloalkyl group, a (C 3 -C 8 )cyclo- alkyl-(C ⁇ -C 6 )alkyl group in which the alkyl moiety is linear or branched, a phenyl group or a phenyl-(C 1 -C 6 )alkyl group in which the alkyl moiety is linear or branched),
  • R 4 represents a hydrogen atom or a group R 3 as defined hereinbefore,
  • the phenyl or phenylalkyl groups may be substituted on the benzene ring by one or more substituents selected from linear or branched ( -C ⁇ alkyl, hydroxy, linear or branched (d-C 6 )alkoxy, amino, linear or branched (C 1 -C 6 )alkylamino, di-(C ⁇ -C 6 )- alkylamino in which each alkyl moiety is linear or branched, NO 2 and halogen atoms,
  • alkyl group may be substituted by one or more substituents selected from hydroxy, carboxy, linear or branched (C 1 -C 6 )alkyl, linear or branched (d-C 6 )alkoxy and halogen atoms,
  • the cycloalkyl and cycloalkylalkyl groups may be substituted on the cyclic moiety by one or more substituents selected from hydroxy, carboxy, linear or branched (C ⁇ -C 6 )- alkoxy and halogen atoms,
  • the compound of formula (I) cannot represent 3-methyl-, 3 -ethyl-, 3,3-dimethyl- or 3,3-diethyl- -6-nitro-phthalide or 3-methyl- or 3,3-dimethyl- -6-amino- phthalide or 3,3-dimethyl-6-(dimethylamino)-phthalide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
  • Preferred compounds of the invention are compounds of formula (I) wherein R 4 represents a hydrogen atom.
  • the group R 1 is preferably a linear or branched (C ⁇ -C 1 )alkyl group and, more especially, the groups methyl, ethyl and R-butyl, or R 1 and R 2 , together with the carbon atom carrying them, form a ring having 5 or 6 carbon atoms.
  • the invention relates to compounds of formula (I) wherein R 3 represents a nitro group or a group NRaR' a (wherein R a and R' a are as defined hereinbefore) such as, for example, the groups amino, formamido, isopropylamino or dimethylamino.
  • the invention relates to compounds of formula (I) that are :
  • the invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material a compound of formula (II) :
  • R 1 and R 2 are as defined hereinbefore,
  • R 1 and R 2 are as defined hereinbefore,
  • R 1 and R 2 are as defined hereinbefore,
  • R 1 , R 2 , R a and R a are as defined hereinbefore,
  • R a is as defined hereinbefore
  • R 1 , R 2 , Z and R' 5 are as defined hereinbefore,
  • R , 1 , R , Z and R a are as defined hereinbefore,
  • R , R a , R' a , R a and Z are as defined hereinbefore,
  • R 1 and R 2 are as defined hereinbefore,
  • R 1 , R 2 , R a and R a are as defined hereinbefore,
  • R 1 , R 2 and R 3 are as defined hereinbefore and R' 4 may take any of the meanings of the group R 3 ,
  • the compounds of formulae (17a) to (I/l) constituting the totality of the compounds of formula (I), which may be purified according to a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and are separated, where appropriate, into their isomers according to a conventional separation technique.
  • Results have shown that they are new calcium antagonists and can be used as a basis for elucidating the anti-epileptic mechanism.
  • Compounds of the invention furthermore exhibit potent neuroprotective effects and cognition-enhancing properties rendering them of use in : - the treatment of cognitive deficiencies associated with ageing and with neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoff s disease and frontal lobe and subcortical dementias,
  • the invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) together with one or more appropriate, inert, non- toxic excipients.
  • pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) and nasal administration, tablets or sugar coated tablets, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc..
  • the dosage used can be adapted to the nature and the severity of the disorder, the administration route and the age and weight of the patient.
  • the dosage varies from 0.01 mg to 1 g per day in one or more administrations.
  • a dry three-necked flask is charged with 16.0 g (0.658 mol) of magnesium turnings, which are covered with anhydrous ether.
  • a small portion of «-butyl bromide is added dropwise to the mixture to initiate the reaction.
  • the addition of M-butyl bromide is continued until the magnesium turnings are digested completely; the total amount of «-butyl bromide added is 82 g (0.599 mol).
  • the reaction mixture is then heated under reflux for 1 hour.
  • To the cooled Grignard reagent there is added, dropwise, a solution of 36.0 g (0.24 mol) of o-phthalaldehydic acid in 200 ml of anhydrous tetrahydrofuran in 1 hour.
  • Boiling point 144-148°C/ 2 mmHg
  • Example 2 Analogously to the method described in Example 4, 3.5 g (0.018 mol) of compound obtained in Example 2 are reduced to give the title compound.
  • Example 7 Analogously to the method described in Example 7, 0.5 g (1.91 mmol) of compound obtained in Example 6 is acetylated to give the title compound. Melting point : 133-134°C Elemental microanalysis :
  • Step A 6-Acetamido-3-butyl-5-nitro-phthalide
  • Step B 6-Amino-3-butyl-5-nitro-phthalide
  • Step B (+)-(3R)-6-Amino-3-butyl-phthalide
  • the acute toxicity was evaluated after oral administration to groups each comprising 8 mice (26 ⁇ 2 grams). The animals were observed at regular intervals during the course of the first day, and daily for the two weeks following treatment.
  • the LDs 0 dose that causes the death of 50 % of the animals ) was evaluated and demonstrated the low toxicity of the compounds of the invention.
  • Compounds of the invention antagonise intracellular Ca +2 level induced by KC1, Bay K 8644 and glutamate. Using patch clamp whole cell recording technique, compounds of the invention are found to be able to reduce the L-type calcium current and to shorten the action potential duration in myocardial cells of guinea pigs and cultured human neuroblastoma cells.
  • the compounds of the invention have been shown to reduce in a concentration-dependent and reversible manner the L-type calcium current and to block the sodium current. These results indicate that the compounds of the invention could be potent L-type calcium channel and sodium channel blockers.
  • Glutamate is a major excitatory neurotransmitter in the central nervous system and there is excessive release of glutamate in the case of cerebral ischemia.
  • Compounds of the invention at concentration of 10 "6 mol/L can remarkably inhibit calcium-dependent and also calcium-independent release of glutamate in synaptosomes.
  • EXAMPLE D Transient global forebrain ischaemia in the Wistar rat
  • Transient forebrain ischaemia was induced by four-vessel occlusion according to the method of Pulsinelli and Brierley (Stroke, 1979, 10 : 267-272).
  • Male Wistar rats (280- 320g) were prepared for forebrain ischaemia under pentobarbital (60 mg/kg i.p.) anaesthesia.
  • the vertebral arteries were definitively occluded by electrocauterisation and atraumatic clamps were placed around the carotid arteries without interrupting the arterial blood flow. The following day, animals were administered, by the i.p.
  • mice Seven days later animals were sacrificed by decapitation, the brains were rapidly removed, and frozen at -30°C in isopentane and stored at -40°C until analysis. Neuronal cell death was assessed by counting viable cells in the CA1 field of the hippocampus in both hemispheres (from 3.8 to 4.2 mm anterior to LA. line) in 7 ⁇ m hematoxylin-eosin-stained brain sections. Results indicate that the compounds of the invention at a dose of 20 mg/kg i.p. possess potent neuroprotective effects that block the neuronal death induced by transient global forebrain ischaemia in the rat.
  • mice Adult male NMRI mice (18-20g) were used. Mice were maintained on an adequate diet and allowed free access to food and water before testing. The drug under study or the carrier was administered by the i.p. or p.o. route 30 min or 60 min before testing, respectively. Then, mice were placed in individual cage units (10x10x10 cm) to avoid group effects. A drop of electrolyte solution (0.9 % sodium chloride solution) was applied to the eyes and an electrical stimulus (20 mA ; 50 Hz) was delivered for 0.5 sec. The animals were restrained only by hand and were released at the moment of stimulation in order to permit observation of the seizure throughout its entire course.
  • electrolyte solution 0.9 % sodium chloride solution
  • the hindleg tonic extensor component was rated present or absent (1 or 0) and was considered to have been suppressed by a drug effect if it did not exceed a 90° angle with the plane of the body.
  • the results indicate that exemplified compounds have potent anticonvulsant effects from 25 to 50 mg kg i.p. and at a dose of 100 mg/kg p.o.
  • EXAMPLE G Social recognition test in the Wistar rat

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Furan Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Medicinal Preparation (AREA)
EP01958282A 2000-06-28 2001-06-27 Substituted phthalides as anti-convulsive drugs Withdrawn EP1320528A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN00119329 2000-06-28
CNB001193295A CN1182127C (zh) 2000-06-28 2000-06-28 新的取代的2-苯并[c]呋喃酮化合物,其制备方法以及包含它们的药物组合物
PCT/IB2001/001535 WO2002000638A2 (en) 2000-06-28 2001-06-27 Substituted phthalides as anti-convulsive drugs

Publications (1)

Publication Number Publication Date
EP1320528A2 true EP1320528A2 (en) 2003-06-25

Family

ID=4587601

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01958282A Withdrawn EP1320528A2 (en) 2000-06-28 2001-06-27 Substituted phthalides as anti-convulsive drugs

Country Status (19)

Country Link
US (1) US6689808B2 (zh)
EP (1) EP1320528A2 (zh)
JP (1) JP2004501909A (zh)
KR (1) KR20030024710A (zh)
CN (2) CN1182127C (zh)
AR (1) AR030239A1 (zh)
AU (1) AU2001280004A1 (zh)
BR (1) BR0112043A (zh)
CA (1) CA2413752A1 (zh)
CZ (1) CZ2003245A3 (zh)
EA (1) EA200300044A1 (zh)
HU (1) HUP0301567A3 (zh)
MX (1) MXPA02012569A (zh)
NO (1) NO20026154L (zh)
NZ (1) NZ523174A (zh)
PL (1) PL359373A1 (zh)
SK (1) SK1062003A3 (zh)
WO (1) WO2002000638A2 (zh)
ZA (1) ZA200210004B (zh)

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Publication number Priority date Publication date Assignee Title
JP4804353B2 (ja) * 2003-05-14 2011-11-02 ディーエスエム アイピー アセッツ ビー．ブイ． 糖尿病の治療及び予防のためのフタリド誘導体の使用
EP1662906A1 (en) 2003-09-23 2006-06-07 DSM IP Assets B.V. Compositions for the treatment and prevention of diabetes mellitus
CN1605336A (zh) * 2003-10-10 2005-04-13 中国医学科学院药物研究所 左旋丁基苯酞在制备预防和治疗脑梗塞的药物中的应用
JP2008502607A (ja) * 2004-06-18 2008-01-31 石薬集団中奇制薬技術（石家庄）有限公司 痴呆の予防および治療におけるＬ−ｎ−ブチルフタリドの適用
CN106074497A (zh) * 2010-01-13 2016-11-09 石药集团恩必普药业有限公司 丁苯酞及其衍生物在制备治疗帕金森病的药物中的应用
CN102260233A (zh) * 2011-05-04 2011-11-30 武汉科技大学 3-丁基-1(3h)-异苯并呋喃酮衍生物及其制备方法
CN105367526B (zh) * 2015-10-14 2017-07-28 济南诚汇双达化工有限公司 一种高纯度正丁基苯酞的制备方法
CN108727352B (zh) * 2017-04-14 2021-04-23 四川大学 一类哌啶烷氨甲酰基苯酞类化合物、其制备方法和用途
PL3845524T3 (pl) * 2018-03-19 2022-10-24 Henan Genuine Biotech Co., Ltd. Związki kwasu benzoesowego i sposób ich wytwarzania oraz ich zastosowania
CN108752300B (zh) * 2018-05-16 2022-03-25 中国科学院昆明植物研究所 苄烯叉苯肽类化合物及其药物组合物和其应用
CN109111415B (zh) * 2018-10-25 2022-08-23 安徽中医药大学 一类石斛生物碱衍生物、制备方法和医药用途
CN112010827A (zh) * 2019-05-28 2020-12-01 四川大学 一类苄胺基苯酞类化合物、其制备方法和用途
CN112010837B (zh) * 2019-05-28 2021-12-17 四川大学 一类吡啶甲胺基苯酞类化合物、其制备方法和用途
CN110452203B (zh) * 2019-08-29 2021-04-13 忻州师范学院 一种1-氧代-1,3-二氢-3-羟基苯并呋喃-5-甲酸的制备方法
CN112794831B (zh) * 2021-04-06 2021-07-27 北京理工大学 3-(3′-羟基丁基)异苯并呋喃-1(3h)-酮衍生物及其组合物、制备方法和用途

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Also Published As

Publication number Publication date
EA200300044A1 (ru) 2003-06-26
PL359373A1 (en) 2004-08-23
SK1062003A3 (en) 2003-05-02
HUP0301567A3 (en) 2005-08-29
MXPA02012569A (es) 2004-05-17
JP2004501909A (ja) 2004-01-22
CZ2003245A3 (cs) 2003-05-14
CA2413752A1 (en) 2002-01-03
WO2002000638A2 (en) 2002-01-03
CN1182127C (zh) 2004-12-29
WO2002000638A3 (en) 2002-05-23
NO20026154D0 (no) 2002-12-20
US6689808B2 (en) 2004-02-10
KR20030024710A (ko) 2003-03-26
NO20026154L (no) 2003-02-20
ZA200210004B (en) 2003-12-10
AR030239A1 (es) 2003-08-13
AU2001280004A1 (en) 2002-01-08
BR0112043A (pt) 2003-10-28
NZ523174A (en) 2004-06-25
WO2002000638A8 (en) 2003-08-28
CN100402515C (zh) 2008-07-16
CN1330069A (zh) 2002-01-09
CN1440398A (zh) 2003-09-03
US20030220393A1 (en) 2003-11-27
HUP0301567A2 (hu) 2003-09-29

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