EP1100484A1 - Antagonistes des recepteurs des monocytes macrophages - Google Patents

Antagonistes des recepteurs des monocytes macrophages

Info

Publication number
EP1100484A1
EP1100484A1 EP99935715A EP99935715A EP1100484A1 EP 1100484 A1 EP1100484 A1 EP 1100484A1 EP 99935715 A EP99935715 A EP 99935715A EP 99935715 A EP99935715 A EP 99935715A EP 1100484 A1 EP1100484 A1 EP 1100484A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
bromo
group
phenylenediamine
dichloro
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Withdrawn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
EP99935715A
Other languages
German (de)
English (en)
Inventor
Joseph Weinstock
Robert G. Franz
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.)
SmithKline Beecham Corp
Original Assignee
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
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1100484A1 publication Critical patent/EP1100484A1/fr
Withdrawn legal-status Critical Current

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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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
    • 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

Definitions

  • Cardiovascular diseases are the leading cause of death in the U.S., accounting annually for more than one million deaths.
  • Atherosclerosis is the major contributor to coronary heart disease and a primary cause of non-accidental death in Western societies. Since the prevention of atherosclerosis is an enormous unmet medical need, considerable effort has been made in defining the etiology and potential treatment of atherosclerosis and its consequences, including myocardial infarction, angina, organ failure and stroke. Despite this effort, there are many unanswered questions including how and when atherosclerotic lesions become life-threatening, the best point of intervention, and how to detect and monitor the progression of lesions.
  • Atherosclerosis There is widespread agreement that multiple risk factors contribute to atherosclerosis including hypertension, elevated total serum cholesterol, high levels of low density lipoprotein (“LDL”) cholesterol, low levels of high density lipoprotein (“HDL”) cholesterol, diabetes mellitus, severe obesity, and cigarette smoking.
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • the initial lesion in atherosclerosis is the fatty streak, which arises from cholesteryl esters maintained as lipid droplets inside macrophage-derived foam cells.
  • Macrophages down-regulate their LDL receptors and instead express mRNA and undergo new protein synthesis for a novel receptor for modified LDL.
  • This receptor recognizes all modified forms of low-density lipoprotein and has come to be known as the macrophage scavenger receptor ("MSR"). If the macrophage is present in an environment that is continually generating modified LDL, it will accumulate lipid droplets of cholosteryl esters, continuing until the macrophage dies from its toxic lipid burden. The released lipid then forms the acellular necrotic core of the atherosclerotic lesion.
  • Macrophage- derived foam cells are concentrated in the shoulders of plaques, where their secreted proteases and collagenases may contribute to plaque rupture which may lead to a fatal thrombotic event.
  • Plaque regression a function of the dynamic balance among initiation, progression, stabilization and removal of plaque constituents, has been unequivocally demonstrated in humans as well as in numerous animal models. Multiple regression studies in non-human primates have shown that even relatively advanced lesions regress over time when atherogenic dietary stimuli are discontinued or pharmacological regimens are initiated.
  • MSR antagonists provide a unique approach towards the pharmacotherapy of cardiovascular diseases such as atherosclerosis, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure, and hypercholesterolemia.
  • the present invention involves phenylenediamine compounds represented by Formula (I) hereinbelow and their use as macrophage scavenger receptor (“MSR”) antagonists which are useful in the treatment of a variety of cardiovascular diseases including but not limited to atherosclerosis, coronary artery disease, renal disease, thrombosis, transient ischemia due to clotting, stroke, myocardial infarction, organ transplant, organ failure and hypercholesterolemia.
  • MSR macrophage scavenger receptor
  • the present invention further provides methods for antagonizing the macrophage scavenger receptor in animals, including humans, comprising administering to an animal in need of treatment an effective amount of a compound of Formula (I), indicated hereinbelow.
  • the present invention further provides methods of inhibiting lipid accumulation within macrophage-derived foam cells.
  • R! is independently selected from the group consisting of hydrogen, alkyl, (Ri) 2 N-alkyl, hydroxyalkyl, carboxy, carboxyalklyl, fluoroalkyl, halo, haloaryl, aryl, heteroaryl, hydroxy, amino, alkylamino, and alkoxy; or R represents a fused ring forming a naphthalene moiety with the six membered aryl ring it substitutes; m is an integer from 1 to 4.
  • R2 is independently selected from the group consisting of hydrogen, R ⁇ -benzamido, R ⁇ - benzyl ether, R ⁇ -benzylamino, amino, halo, hydroxy, alkoxy, alkyl, fluoroalkyl, cyano, nitro, aryloxy, nitroalkyl, aryl, and 1,2-benzo; or the R ⁇ moiety represents a fused ring forming a napthalene ring with the six membered aryl ring it substitutes; and n is an integer from 1 to 3.
  • R ⁇ is selected from the group consisting of hydrogen, 5-trifluoromethyl, 5-chloro, 5-bromo, 3-bromo, 4-bromo, 5-bromo-3-phenyl, 5-iodo, 5-iodo-3-phenyl, 2- phenyl, 3-phenyl, 5-phenyl and 3-methoxy. More preferably, R ⁇ is 5-trifluoromethyl or 5- bromo.
  • any R ⁇ aryl substituents are selected from the group consisting of hydroxy, halo, aryl, alkyl, cyano, nitro, R* ⁇ benzamidyl, alkoxy and aryloxy. More preferably, R ⁇ is selected from the group consisting of 2-chloro, 3,4-dichloro, 4,5-dichloro, 3-methoxy, 2-isopropyl, 3-cyano, 4-butyl, 2-nitro, 2-phenoxy, 2-nitro-4-methyl, 2-phenyl, 4-phenyl, 2-benzamidyl, 1,2-benzo. Most preferably, R ⁇ is 4,5-dichloro, 2-benzamidyl, 4- bromo, 4-phenyl or 4-butyl.
  • Particularly preferred compounds useful in the present invention include: bis-N,N'-(5-bromo-2-hydroxybenzoy l)-4,5-dichloro- 1 ,2-pheny lenediamine, bis-N,N'-(5- bromo-2-hydroxybenzoyl)- 1 ,2-phenylenediamine, bis- N,N'-(5-trifluoromethyl-2- hydroxybenzoyl)- 1 ,2-pheny lenediamine, bis-N,N'-(5-trifluoromethyl-2-hydroxybenzoy 1)- 4,5-dichloro- 1 ,2-phenylenediamine, bis-N,N'-(3-phenyl-2-hydroxybenzoyl)-4,5-dichloro- 1 ,2-phenylenediamine, and bis-N,N'-(3-phenyl-2-hydroxybenzoyl)- 1 ,2-phenylenediamine.
  • the present compounds can also be formulated as pharmaceutically acceptable salt
  • salts for use when basic groups are present include acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, /?-toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • the present invention provides compounds of Formula (I) above which can be prepared using standard techniques. An overall strategy for preparing preferred compounds described herein can be carried out as described in this section. The examples which follow illustrate the synthesis of specific compounds. Similar 1,2-phenylene diamide compounds have been reported by Y. A. (2004) and A. H. M. Elwahy; Synthesis, 503 (1993); F. C.
  • the amine can be reacted with a 2-methoxybenzoyl chloride to give the bis-amide, and the methoxy ether cleaved to the phenol by a variety of known cleavage reagents. Boron tribromide is especially effective.
  • This procedure can be used to conveniently obtain unsymmetrical bis-amides by using different salicylic acids for the first and seacond stages of the sequence.
  • This procedure can also be used to prepare 1,3- and 1 ,4-bis-amides by starting with 3- or 4-nitroanilines in place of the 2-nitroanilines described above.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal), or transmucosal administration.
  • oral administration is preferred.
  • the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.
  • injection parenteral administration
  • the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the compounds may be formulated in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.
  • the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • the amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC50, EC50, tne biological half-life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.
  • Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered.
  • the composition is in unit dosage form.
  • a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered.
  • dosing is such that the patient may administer a single dose.
  • Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula (I).
  • a topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I).
  • the active ingredient may be administered from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
  • treatment of a disease includes, but is not limited to prevention, retardation and prophylaxis of the disease.
  • the MSR receptors described in the present application belong to a recently classified group designated the SR-A group and exist in two forms, type A-I and type A-II, which arise through differential exon splicing of a single gene.
  • the terms “MSR” and “SR- A” are used interchangeably in the present application.
  • Composition of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used.
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose. No unacceptable toxological effects are expected when compounds of the present invention are administered in accordance with the present invention.
  • the medium is replaced with 500 ⁇ l fresh serum-free medium containing 2 mg/ml BSA and 125[I]-AcLDL (iodinated acetylated low density lipoprotein) at 5 ⁇ g/ml, and cells are incubated at 37C for 5 hours. After this suitable period for ligand degradation, cells are removed to a 4C cold room. Supernatant is removed into trichloroacetic acid, and the mixture is centrifuged. The supernatant is chloroform- extracted in order to isolate 125[I]-monoiodotyrosine, the degradation product of 125[I]- AcLDL, and portions are counted to determine degradative activity.
  • 125[I]-AcLDL iodinated acetylated low density lipoprotein
  • cell monolayers are washed and incubated at 4C with ice-cold buffer "A" containing 150 mM NaCl, 50 mM Tris-HCl, and 2 mg/ml BSA, pH 7.4, to eliminate nonspecifically bound counts.
  • Cells are washed three times rapidly with 1 ml, incubated twice for 10 min each on a rotary shaker in 1 ml buffer A, then washed twice rapidly in 1 ml buffer A without BSA. After aspiration of all wash buffer, cells are lysed in 0.1 N NaOH and removed to counting vials for determination of binding/uptake and subsequent protein determination (Pierce BCA protein assay).
  • the present actives yield IC50 values of ⁇ 50 um in degradation assays and ⁇ 100um in binding/uptake assays.
  • the fluorescent compound Dil-AcLDL (l,l '-dioctadecyl-3,3,3',3'- tetramethylindocarbocyanine perchlorate-labeled LDL) has also been shown to be a useful tool in assessing activity of the macrophage scavenger receptor (Freeman et al., Proc. Natl. Acad. Sci., USA, 88:4931-4935 (1991); Penman et al., J. Biol. Chem., 266:23985-23993 (1991)).
  • HEK 293 cells transfected with SR-AI were used, although both SR-AI and SR-AII appeared to have equivalent activity in all studies performed. Briefly, HEK 293 cells were seeded at 2 x 10 ⁇ cells/ well in a 96- well plate in EMEM with 2mM glutamine, 10%FBS and 0.4mg/ml geneticin. The assay was standardized and optimized, and testing was performed in serum-free EMEM containing 2mg/ml bovine serum albumin.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Vascular Medicine (AREA)
  • Transplantation (AREA)
  • Obesity (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des antagonistes des récepteurs des monocytes macrophages. L'invention traite également de procédés permettant de traiter des maladies cardio-vasculaires, et consistant à administrer les composés selon l'invention qui inhibent l'accumulation des lipides dans les cellules spumeuses dérivées des macrophages.
EP99935715A 1998-07-20 1999-07-20 Antagonistes des recepteurs des monocytes macrophages Withdrawn EP1100484A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US9336198P 1998-07-20 1998-07-20
US93361P 1998-07-20
PCT/US1999/016347 WO2000003704A1 (fr) 1998-07-20 1999-07-20 Antagonistes des recepteurs des monocytes macrophages

Publications (1)

Publication Number Publication Date
EP1100484A1 true EP1100484A1 (fr) 2001-05-23

Family

ID=22238497

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99935715A Withdrawn EP1100484A1 (fr) 1998-07-20 1999-07-20 Antagonistes des recepteurs des monocytes macrophages

Country Status (4)

Country Link
EP (1) EP1100484A1 (fr)
JP (1) JP2003521446A (fr)
CA (1) CA2338122A1 (fr)
WO (1) WO2000003704A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2001264286A1 (en) * 2000-06-16 2001-12-24 Chugai Seiyaku Kabushiki Kaisha Preventives/remedies for granuloma
JP2004530654A (ja) 2001-02-23 2004-10-07 ブリストル−マイヤーズ・スクイブ・ファーマ・カンパニー アテローム硬化症および脆弱性プラークを画像診断するための標識マクロファージスカベンジャー受容体拮抗薬
AUPR738301A0 (en) * 2001-08-30 2001-09-20 Starpharma Limited Chemotherapeutic agents
US6897220B2 (en) 2001-09-14 2005-05-24 Methylgene, Inc. Inhibitors of histone deacetylase
CN101851173A (zh) 2001-09-14 2010-10-06 梅特希尔基因公司 组蛋白脱乙酰化酶抑制剂
AU2006252047B2 (en) * 2001-09-14 2010-02-11 Methylgene Inc. Inhibitors of histone deacetylase
US7868204B2 (en) 2001-09-14 2011-01-11 Methylgene Inc. Inhibitors of histone deacetylase
US7868205B2 (en) 2003-09-24 2011-01-11 Methylgene Inc. Inhibitors of histone deacetylase
US7253204B2 (en) 2004-03-26 2007-08-07 Methylgene Inc. Inhibitors of histone deacetylase
AU2007234843B2 (en) 2006-04-07 2013-07-11 Methylgene Inc. Inhibitors of histone deacetylase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0003704A1 *

Also Published As

Publication number Publication date
JP2003521446A (ja) 2003-07-15
WO2000003704A1 (fr) 2000-01-27
CA2338122A1 (fr) 2000-01-27

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