WO2002096890A2 - Processus chimiques et produits intermediaires - Google Patents

Processus chimiques et produits intermediaires Download PDF

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Publication number
WO2002096890A2
WO2002096890A2 PCT/GB2002/002511 GB0202511W WO02096890A2 WO 2002096890 A2 WO2002096890 A2 WO 2002096890A2 GB 0202511 W GB0202511 W GB 0202511W WO 02096890 A2 WO02096890 A2 WO 02096890A2
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Prior art keywords
atom
compound
alkyl
ring
process according
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PCT/GB2002/002511
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English (en)
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WO2002096890A3 (fr
Inventor
Daniel Levin
Garnet Edward Howells
Murray Watson Cuthbert
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to AU2002314299A priority Critical patent/AU2002314299A1/en
Publication of WO2002096890A2 publication Critical patent/WO2002096890A2/fr
Publication of WO2002096890A3 publication Critical patent/WO2002096890A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B41/00—Formation or introduction of functional groups containing oxygen
    • C07B41/04—Formation or introduction of functional groups containing oxygen of ether, acetal or ketal groups

Definitions

  • the invention relates to chemical processes, and in particular to processes which involve reactions known as Mitsunobu reactions.
  • the processes of the invention are useful in the preparation of intermediates used in the production of certain oxazolidinone anti-Gram positive bacterial agents.
  • the Mitsunobu reaction is a widely applicable reaction which allows the coupling of nucleophiles (NuH) to alcohols and particularly secondary alcohols. It is described for example in Progress in the Mitsunobu reaction: a Review, by D.L. Hughes in Organic Preparations and Procedures International, 28, (2) pl27-164. A particular example of such as reaction is described by Nakamura et al. Tet. Lett. 31, 5, 699-702 (1990). Where the secondary alcohol is chiral, a clean inversion of the stereochemistry takes place.
  • the reaction utilises a redox system made up of an activating agent such as an azodicarboxylate and a trisubstituted phosphine or phosphite.
  • the redox system is completed by adding the activating agent to a solution of the remaining components of the reaction mixture (i.e. the nucleophile, the alcohol and the trisubstituted phosphine.
  • the nucleophiles are multidentate, in that they contain more than one nucleophilic site, for example, both an oxygen and a nitrogen atom, it has been recognised that coupling may take place at both sites. This leads to a mixture of N- and O- linked products for instance, although generally the O-linked product is predominant.
  • Our International Patent Application No. WO 99/64417 describes a new class of antibacterial oxazolidinone compounds which are effective as anti-Gram positive bacterial agents, and certain processes for their preparation. These include compounds of formula (I):
  • HET is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)aIkylamino, (1-
  • R 2 and R 3 are independently hydrogen or fluoro;
  • Rep is of the formula R 13 CO- (wherein R 13 is (l-lOC)alkyl substituted by two or more hydroxy groups; 2 of which are in a 1,2-diol orientation, ie. there is a terminal primary alcohol with an adjacent secondary alcohol), or pharmaceutically-acceptable salts, or in-vivo- hydrolysable esters thereof.
  • HET is (unsubstituted) isoxazol-3-yl, 1,2,4- oxadiazol-3-yl, isothiazol-3-yl or l,2,5-thiadiazol-3-yl are preferred.
  • those of formula (I-l) are the pharmaceutically active anti-bacterial enantiomer.
  • the pure enantiomer depicted in (I-l), or mixtures of the 5R and 5S enantiomers, for example a racemic mixture are included in WO 99/64417. If a mixture of enantiomers is used, a larger amount (depending upon the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer.
  • the enantiomer depicted below is the 5R enantiomer.
  • some compounds of the formula (I) and (I-l) may have other chiral centres, and such optical and diastereo-isomers, and racemic mixtures may possess antibacterial activity. It is well known in the art how to prepare optically-active forms (for example by resolution of the racemic form by recrystallisation techniques, by chiral synthesis, by enzymatic resolution, by biotransformation or by chromatographic separation) and how to determine antibacterial activity.
  • HA (where R 2 , R 3 and HET are as defined in relation to formula (I)) are formed by adding ' diisopropylazodicarboxylate (DIAD) to a solution of a compound of formula (IHA)
  • DIAD diisopropylazodicarboxylate
  • OVA (where HET is as described above); and triphenylphosphine, in tetrahydrofuran; and thereafter, if necessary, removing any protecting group R 4 .
  • Removal of protecting groups R 4 are carried out using conventional methods.
  • Reference Example 6 of WO 99/64417 describes the removal of a benzyl protecting group R 4 by reaction of a solution of the isolated compound of formula (HA) in dichloromethane with 1-chloroethyl chloroformate.
  • a method of coupling an alcohol group of an organic compound to a multidentate nucleophilic compound comprises adding to a reaction vessel containing an activating agent, said nucleophilic compound, said alcohol and a trisubstituted phosphine or trisubsituted phosphite, wherein the trisubstituted phosphine or trisubstituted phosphite and the activating agent together form a redox system which is able to operate a Mitsunobu reaction, resulting in formation of a coupled compound.
  • Suitable redox sytems are known in the art and are described for example in the review by D.L. Hughes et al (supra.) and "The Mitsunobu Reaction” by D.L. Hughes, Org. React. (N. Y.) (1992), 42 335-656.
  • the activating agent is an azodicarboxylate, in particular a di(l-6C)alkylazodicarboxylate (such as DIAD as mentioned above, and diethylazodicarboxylate (DEAD)) or a diheterocyclic system (such as 1,1'- (azodicarbonyl)dipiperidine) or a tetra alkyl azodicarboxylate such as N,N, N'N'-tetramethyl- azodicarboxylate or N,N,N',N'tetraisopropylazodicarboxylates.
  • a di(l-6C)alkylazodicarboxylate such as DIAD as mentioned above, and diethylazodicarboxylate (DEAD)
  • a diheterocyclic system such as 1,1'- (azodicarbonyl)dipiperidine
  • a tetra alkyl azodicarboxylate such as N,N, N'N'-
  • Suitable substituents for the phosphine and phosphite groups are optionally substituted aryl, alkyl, or aralkyl groups. Suitable optional substitutents for such groups are an amino, or mono- or dialkyl amino groups such as dimethyl amino. Particular examples are triphenylphosphine, tributylphosphine, methyldiphenylphosphine, dimethylaminophenyldiphenyl phosphine and triethylphosphite. A preferred example however is triphenylphosphine.
  • alkyl refers to straight or branched alkyl chains suitably containing from 1 to 10 and preferably from 1 to 6 carbon atoms.
  • aryl includes phenyl and napthyl.
  • aralkyl refers to alkyl groups substituted with aryl groups, such as benzyl.
  • heterocyclic refers to rings of up to 10 and preferably up to 7 atoms which include one or more heteroatoms selected from oxygen, nitrogen or sulphur. The rings may be saturated or unsaturated, but are preferably saturated rings such as piperidine rings.
  • the alcohol used in the reaction may be any compound of the desired structure. Where these contain nucleophilic groups, these may be protected using conventional methods.
  • the multidentate ligand may be of any desired structure, depending upon the nature of the final product required. These may be chemical products such as pharmaceuticals, or intermediates to chemical products.
  • the invention provides a process for preparing a compound of formula (D) or a hydrate salt thereof,
  • n 0 or 1
  • Y is an anion
  • R 8 is -OR 9 , -SR 9 , -NHR 10 or -NR ⁇ R 12 , where
  • R 9 is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; or
  • R 9 is a C-linked 6-membered heteroaryl ring containing 1 or 2 nitrogen heteroatoms, which ring is optionally substituted on any available C atom (provided that when the N atom is adjacent to the link, there is no substitution on any C atom that is adjacent to this N atom) by 1, 2 or 3 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy, (l-4C)alkoxycarbonyl and halogen;
  • R 10 is is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (1- 4C)alkoxy, (l-4C)alkoxycarbonyl and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; or R 10 is a C-linked 6-membered heteroaryl ring containing 2 or 3 nitrogen heteroatoms, which ring is optionally substituted on any available C atom by 1, 2 or 3 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy, (l-4C)alkoxycarbonyl and halogen;
  • R 11 and R 12 together with the nitrogen atom to which they are attached form a 5-membered heteroaryl ring, containing either (i) 1 to 3 further nitrogen heteroatoms or (ii) a further heteroatom selected from O and S together with an optional further nitrogen heteroatom; which ring is optionally substituted on a C atom by an oxo or thioxo group; and/or the ring is optionally substituted on a C atom by 1 or 2 (l-4C)alkyl groups; and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; or R n and R 12 together with the nitrogen atom to which they are attached form a 6-membered heteroaryl ring containing up to three nitrogen heteroatoms in total (including the linking heteroatom), which ring is substituted on a suitable C atom by oxo or thioxo and optionally substituted on any available C atom by 1 or 2 (l-4C)al
  • the enhancement in ratio can be significantly greater, for example in the order of 50:1 of the desired isomer:unwanted isomer.
  • reagents (i), (ii) and (iii) above are premixed and added together to a solution of the activating agent.
  • the reaction between the compound of formula (HI) and (IV) is suitably effected in an organic solvent such as tetrahydrofuran.
  • organic solvent such as tetrahydrofuran.
  • the amount of activating agent such as diisopropylazodicarboxylate used in the process is greater than the stoichiometric amount required.
  • the amount of activating agent such as diisopropylazodicarboxylate used in the process is greater than the stoichiometric amount required.
  • at least 1.4equivalents of activating agent is used for every one equivalent of the alcohol, which in this case is of formula (HI).
  • an excess of the phosphine or phosphite such as triphenylphosphine is included in the reaction mixture, for example at least 1.55equivalents to the amount of alcohol, such as the alcohol of formula (HI).
  • Preferred compounds of formula (H) are as described in WO 99/64417.
  • R 8 is a group -NHR 10 and methods of preparation are shown in WO00/21960.
  • Particular examples of R 10 are isoxazol-3-yl, isoxazol-5-yl, l,2,4-oxadiazol-3-yl, isothiazol-3-yl, l,2,4-thiadiazol-3-yl or l,2,5-thiadiazol-3- yi.
  • R 9 is a C-linked
  • 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl.
  • R 8 is a group OR 9 .
  • a particular example of a group R 9 is an isoxazole group, and particularly a isoxazol-3-yl.
  • a particular example of a compound of formula (IV) is 3-hydroxyisoxazole.
  • This compound is suitably added to the reaction mixture in the form of a solution in an organic solvent such as butyronitrile.
  • R 2 and R 3 are fluorine.
  • R 4 is a protecting group such as benzyl.
  • Removal of any group R 4 is suitably effected directly, in situ, using conventional methods.
  • a benzyl protecting group may be removed by formation of an intermediate carbamate using diisopropylethylamine (DIPEA) and 1- chloroethylchloroformate, and subsequently acidifying the carbamate using a mineral acid such as hydrochloric acid.
  • DIPEA diisopropylethylamine
  • 1- chloroethylchloroformate 1- chloroethylchloroformate
  • Y will be a halide such as chloride, fluoride, bromide or iodide, but may be other salt forms such as sulphates, acetates such as trifluoroacetate, depending upon the particular acid used.
  • Y may be changed after production to other anions, using conventional methods.
  • Recrystallisation of the product from non-aqueous organic solvents or solvent mixtures has been found to give only a small or negligable purification in terms of the isomer ratio enhancement.
  • the applicants have surprisingly found that recrystallisation from water or from solvent/water mixtures (step b) so as to crystallise the product as a hydrate, gives unexpectedly high differentiation between isomers. This is believed to be due to significantly different crystal packing between isomers, when present as their hydrates.
  • the resultant hydrate salt can then be used in the subsequent processing to produce a compound of formula (H).
  • Suitable solvents for use in the solvent/water mixtures include water miscible or immiscible solvents. Examples include acetone, ethyl acetate or alcohols, such as alkyl alcohols including butanol, methanol, ethanol or mixtures such as Industrial Methylated Spirit 74 op (IMS). Hydrates of compounds of formula (H) are novel and so form a further aspect of the invention. It is to be understood that the invention encompasses both stoichiometric and non- stoichiometric hydrates. Preferably the water of hydration content of the hydrate is approximately 1 - 5% w/w. More preferably the water of hydration content is approximately 4% w/w.
  • a particularly preferred hydrate of a compound of formula (H) is a hydrated form of 5(R)-Isoxazol-3-yloxymethyl-3-(4-(l,2,5,6-tetrahydropyrid-4-yl-3,5- difluorophenyl)oxazolidin-2-one, preferably when the water of hydration content of the hydrate is 4% w/w.
  • a further aspect of the invention comprises a process for purifying a compound of formula (H) as defined above, said method comprising dissolving the compound in water or water in admixture with a further solvent, and allowing the hydrate salt to crystallise therefrom.
  • Suitable further solvents are those described above in relation to the water/solvent mixtures.
  • Compounds of formula (HI) and (IV) are either known compounds or they may be prepared from known compounds by conventional methods.
  • Diisopropyl azodicarboxylate (DIAD) 49.7ml was added to tetrahydrofuran (200ml) contained in a first reaction vessel. The stirred contents of the vessel were cooled to -5°C.
  • the vessel was then cooled to ⁇ 30°C and a solution of 3-hydroxyisoxazole in butyronitrile (194.2g, 8.04%w/w, 1.05mol eq, prepared as described below) added in a single portion.
  • the contents of the second vessel were then transferred to the first vessel via a jacketed dropping funnel maintained at a temperature of 25-28°C over a period of 3 hours.
  • the product is a solution of the oxaisoxazole in the above scheme.
  • Hydroxylamine hydrochloride (59.4g) was dissolved in water (360ml) at -5°C under an inert atmosphere.
  • Sodium hydroxide (10.8N, 167 ml, 2.1 mol eq) was added to the solution via a pressure equalised funnel, maintaining the temperature below -3°C.
  • Water 45ml is added through the funnel and the resulting clear solution warmed to 12°C over 15 minutes.
  • a solution of ethyl propiolate (79.7g, 0.95 mol eq) in tetrahydrofuran (THF) (120ml) is added to the first solution at a uniform rate, maintaining the temperature of the first solution below 15°C.
  • the solution is warmed to 20°C over 15 minutes.
  • THF (30ml) is added, the solution warmed to 55°C and maintained at this temperature for 3 hours, then cooled to 20°C over 1 hour and may be held at this temperature for up to 16 hours.
  • the solution is cooled to -5°C before addition of concentrated hydrochloric acid (90ml) through a pressure equalised funnel, maintaining the temperature below 3°C.
  • the resulting mixture has a pH of 0.5.
  • Water (10ml) is added through the funnel and the mixture warmed to 20°C.
  • THF (90ml) and butyronitrile (300ml) are added and the mixture agitated for 10 minutes.
  • the aqueous layer is separated, washed with butyronitrile (300ml) and the combined organic layers washed with 2M hydrochloric acid (400ml) (10 minute agitation of the mixture).
  • the organic layer is diluted with butyronitrile (600ml) and the solution concentrated by reduced pressure distillation at 60°C until the volume is equal to that of the reaction mixture prior to addition of THF/butyronitrile. Addition of butyronitrile and distillation may be repeated such that same final volume is obtained and the water content of the solution is 0.05-0.07% w/w maximum.
  • the strength of the resulting hydroxyisoxazole solution is calculated to ensure correct addition to the process described above; the solution strength is typically approximately 8% w/w.
  • Example 2 The title compound, prepared as described in Example 1 (lOOg) was added to water (200ml) and warmed to 80°C with stirring to form a solution. The contents were held at 80°C for 10 minutes and then filtered hot. The solution was cooled to allow the product crystallise.
  • the desired product in the form of the hydrate salt was isolated by filtration, washed with water and dried. (78.1g, 83.1% yield).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne un procédé de couplage d'un groupe alcool d'un composé organique à un composé nucléophile multicoordinant. Ce procédé consiste à ajouter à une cuve à réaction contenant un agent activant ce composé nucléophile, l'alcool et une phosphine trisubstituée ou un phosphite trisubstitué. Selon ce procédé, la phosphine trisubstituée ou le phosphite trisubstitué et l'agent activant forment ensemble un système d'oxydoréduction qui peut effectuer une réaction de Mitsunobu, ce qui permet de former un composé couplé.
PCT/GB2002/002511 2001-06-01 2002-05-29 Processus chimiques et produits intermediaires WO2002096890A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002314299A AU2002314299A1 (en) 2001-06-01 2002-05-29 Regioselective mitsunobu reaction, particularly for preparing bactericidal oxazolidinones

Applications Claiming Priority (2)

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GB0113299.2 2001-06-01
GB0113299A GB0113299D0 (en) 2001-06-01 2001-06-01 Chemical process & intermediates

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WO2002096890A3 WO2002096890A3 (fr) 2003-04-10

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6969726B2 (en) 2003-06-03 2005-11-29 Rib X Pharmaceuticals Inc Biaryl heterocyclic compounds and methods of making and using the same
US7022705B2 (en) 2001-10-25 2006-04-04 Astrazeneca Ab Isoxazoline derivatives useful as antimicrobials
US7091196B2 (en) 2002-09-26 2006-08-15 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
US7129259B2 (en) 2003-12-17 2006-10-31 Rib-X Pharmaceuticals, Inc. Halogenated biaryl heterocyclic compounds and methods of making and using the same
US7199143B2 (en) 2002-02-28 2007-04-03 Astrazeneca Ab Chemical compounds
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US7473699B2 (en) 2002-02-28 2009-01-06 Astrazeneca Ab 3-cyclyl-5-(nitrogen-containing 5-membered ring)methyl-oxazolidinone derivatives and their use as antibacterial agents
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same
US8324398B2 (en) 2003-06-03 2012-12-04 Rib-X Pharmaceuticals, Inc. Process for the synthesis of biaryl oxazolidinones
US8399660B2 (en) 2005-06-08 2013-03-19 Rib-X Pharmaceuticals, Inc. Process for the synthesis of triazoles

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WO1999064417A2 (fr) * 1998-06-05 1999-12-16 Astrazeneca Ab Composes chimiques
WO2000021960A1 (fr) * 1998-10-09 2000-04-20 Astrazeneca Ab Heterocyclyl amino methyloxa zolidinones comme agents antibacteriens
WO2001081350A1 (fr) * 2000-04-25 2001-11-01 Astrazeneca Ab Derives d'oxazolidinone ayant une activite antibiotique

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WO2000021960A1 (fr) * 1998-10-09 2000-04-20 Astrazeneca Ab Heterocyclyl amino methyloxa zolidinones comme agents antibacteriens
WO2001081350A1 (fr) * 2000-04-25 2001-11-01 Astrazeneca Ab Derives d'oxazolidinone ayant une activite antibiotique

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US7022705B2 (en) 2001-10-25 2006-04-04 Astrazeneca Ab Isoxazoline derivatives useful as antimicrobials
US7199143B2 (en) 2002-02-28 2007-04-03 Astrazeneca Ab Chemical compounds
US7473699B2 (en) 2002-02-28 2009-01-06 Astrazeneca Ab 3-cyclyl-5-(nitrogen-containing 5-membered ring)methyl-oxazolidinone derivatives and their use as antibacterial agents
US7091196B2 (en) 2002-09-26 2006-08-15 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
US7148219B2 (en) 2003-06-03 2006-12-12 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US6969726B2 (en) 2003-06-03 2005-11-29 Rib X Pharmaceuticals Inc Biaryl heterocyclic compounds and methods of making and using the same
US7456206B2 (en) 2003-06-03 2008-11-25 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US7705026B2 (en) 2003-06-03 2010-04-27 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US8324398B2 (en) 2003-06-03 2012-12-04 Rib-X Pharmaceuticals, Inc. Process for the synthesis of biaryl oxazolidinones
US8895741B2 (en) 2003-06-03 2014-11-25 Melinta Therapeutics, Inc. Process for the synthesis of biaryl oxazolidinones
US9550783B2 (en) 2003-06-03 2017-01-24 Melinta Therapeutics, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US7129259B2 (en) 2003-12-17 2006-10-31 Rib-X Pharmaceuticals, Inc. Halogenated biaryl heterocyclic compounds and methods of making and using the same
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same
US8841263B2 (en) 2004-02-27 2014-09-23 Melinta Therapeutics, Inc. Macrocyclic compounds and methods of making and using the same
US8399660B2 (en) 2005-06-08 2013-03-19 Rib-X Pharmaceuticals, Inc. Process for the synthesis of triazoles
US8796465B2 (en) 2005-06-08 2014-08-05 Melinta Therapeutics, Inc. Process for the syntheses of triazoles
US9376400B2 (en) 2005-06-08 2016-06-28 Melinta Therapeutics, Inc. Process for the synthesis of triazoles

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AU2002314299A1 (en) 2002-12-09
WO2002096890A3 (fr) 2003-04-10

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