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WO2007017546A2 - Procede d'obtention de derives de la triptamine - Google Patents

Procede d'obtention de derives de la triptamine Download PDF

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Publication number
WO2007017546A2
WO2007017546A2 PCT/ES2006/000465 ES2006000465W WO2007017546A2 WO 2007017546 A2 WO2007017546 A2 WO 2007017546A2 ES 2006000465 W ES2006000465 W ES 2006000465W WO 2007017546 A2 WO2007017546 A2 WO 2007017546A2
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WO
WIPO (PCT)
Prior art keywords
formula
compound
ethyl
reaction
vii
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PCT/ES2006/000465
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English (en)
Spanish (es)
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WO2007017546A3 (fr
Inventor
José Vicente Murillo Garrido
Jorge MARTÍN JUÁREZ
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Ragactives SL
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Ragactives SL
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Publication of WO2007017546A3 publication Critical patent/WO2007017546A3/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention relates to a process for obtaining triptamine derivatives, their solvates, hydrates or their pharmaceutically acceptable salts, as well as some of the intermediates of said process.
  • Triptamine derivatives including Zolmitriptan, the international common denomination of compound (4S) -4 - [[3- [2- (dimethylamino) ethyl) -lH-indole-5-yl] methyl ] -2-oxazolidinone, and Rizatriptan, the international common denomination of compound 3- [2- (dimethylamino) ethyl)] - 5- (l // - l, 2,4-triazol-l-ylmethyl) indole, are products with an exceptional agonist activity by receptors similar to 5-HTi, in addition to presenting excellent absorption after oral administration. These compounds have proven particularly useful in the treatment of migraine, cluster headache and headache associated with vascular disorders.
  • the invention relates to a process for obtaining a tryptamine derivative of formula (I) (defined below) comprising the decarboxylation of a compound of formula (VI) (defined below) and subsequent aminomethylation of the intermediate obtained.
  • the invention relates to a compound of formula (IV) (defined below), a compound of formula (V) (defined below) and a compound of formula (VI) (defined below). Said compounds of formula (IV), (V) and (VI) can be used in the synthesis of the compounds of formula (I).
  • the invention relates to a process for obtaining tryptamine derivatives of formula (I) comprising the use of said compounds of formula (IV), (V) and (VI).
  • the invention relates to a process, hereinafter process of the invention [1], for obtaining a tryptamine derivative of formula (I)
  • X is O, NH, S or CH 2 , its enantiomers or mixtures thereof, or its solvates, hydrates or salts, which comprises a) decarboxylating a compound of formula (VI)
  • the first step [step a)] of the process of the invention [1] consists of decarboxylation of the carboxylic acid group located in position 2 of the indole [compound of formula (VI)].
  • Said decarboxylation reaction can be carried out by any conventional method, for example, by treatment with an acid, advantageously, a strong acid.
  • an acid advantageously, a strong acid.
  • this reaction can be performed using a mixture of appropriate acids.
  • the compound of formula (VI) will, in general, be dissolved or suspended in a reaction medium comprising said acid, for example, an aqueous solution of sulfuric acid, although other media and acids may always be used.
  • the decarboxylation reaction can be carried out at a temperature within a wide range, for example, at a temperature between room temperature (typically between 18 0 C and 22 0 C) and reflux temperature.
  • the decarboxylation of the compound of formula (VI) is carried out by treating the compound of formula (VI) with sulfuric acid, in aqueous solution, at the reflux temperature.
  • the compound of formula (VI) can be obtained from a compound of formula (II) by reaction with a compound of formula (III) through the intermediates of formulas (IV) and (V), as shown in Reaction Scheme I and described below.
  • the second stage [step b)] of the process of the invention [1] consists of a methylation of the amino group (-NH 2 ).
  • Said aminomethylation can be carried out by any of the methods known to a person skilled in the art, for example, by reaction with a methyl halide or, preferably, by reductive methylation.
  • this aminomethylation step is carried out by reductive methylation by reacting the compound of formula (VII) with formaldehyde in the presence of a reducing agent and an acid, as shown below:
  • any appropriate reducing agent can be used; however, in a particular embodiment, as a reducing agent, a hydride, such as sodium cyanoborohydride, sodium borohydride together with Ti (OiPr) 4 , etc. can be employed, among others.
  • a hydride such as sodium cyanoborohydride, sodium borohydride together with Ti (OiPr) 4 , etc.
  • the acid any suitable acid can be used, for example, an organic acid such as formic acid, acetic acid, etc.
  • the reductive methylation reaction is carried out in a solvent.
  • any solvent in which the compound of formula (VII) is soluble or dispersible can be used; by way of illustration, not limitation, alcohols and solvents miscible with water can be used, such as tetrahydrofuran, dimethylformamide, etc., preferably alcohols;
  • the solvent is an alcohol, for example, an alcohol of five or less carbon atoms, for example, methanol, etc., although other alcohols can also be used.
  • This reducing methylation reaction can be carried out at a temperature within a wide range, for example, at a temperature between -1O 0 C and + 5O 0 C, preferably between 15 ° C and 4O 0 C, more preferably , between 2O 0 C and 3O 0 C.
  • this reductive methylation reaction is carried out by treating the compound of formula (VII) in methanol with aqueous formaldehyde, sodium cyanoborohydride and acetic acid.
  • this aminomethylation step [step b)] is carried out by a methylation reaction by reacting the compound of formula (VII) with a methyl halide, such as methyl bromide, methyl iodide, etc.
  • a methyl halide such as methyl bromide, methyl iodide, etc.
  • This methylation reaction is carried out in a solvent.
  • Any solvent in which the compound of formula (VII) is soluble or dispersible can be used; by way of illustration, not limitation, tetrahydrofuran, dimethylformamide, alcohols, etc. can be used.
  • This methylation reaction may be conducted at a temperature within a wide range, for example, at a temperature between -10 0 C and + 5O 0 C, preferably between 0 0 C and 4O 0 C, more preferably, between 15 0 C and 25 ° C.
  • the compound of formula (I) has a chiral carbon and, therefore, exists either in the form of its isolated (R) or (S) enantiomers or in the form of mixtures of said enantiomers.
  • the term "enantiomer mixtures" or “enantiomeric mixtures” includes both racemic mixtures and enriched mixtures in any one of the enantiomers.
  • the enantiomers (R) and (S) of the compound of formula (I) obtained can be separated by conventional methods of resolving mixtures of enantiomers, for example, by fractional crystallization, chromatographic methods, etc.
  • the resolution of the mixture of enantiomers can be carried out by any conventional method, for example, using chiral chromatographic columns or by fractional crystallization of salts of the corresponding enantiomers with the appropriate optically active (chiral) acids; in this case, the salt corresponding to the desired enantiomer can be recrystallized as many times as necessary until the desired enantiomer is obtained with the desired purity.
  • the compound of formula (I) obtained by the process provided by this invention is obtained in the form of a mixture of enantiomers, for example, in the form of a racemic mixture. Therefore, if desired, the mixture of enantiomers obtained can be resolved into their corresponding enantiomers to obtain the desired enantiomer.
  • said enantiomer is the enantiomer (S).
  • the desired enantiomer of the compound of formula (I) can be obtained by an enantioselective synthesis, from the starting product [compound of formula (VI)] with the appropriate sterochemistry, by a procedure that preserves the optical isometry until the end.
  • the starting product with the api'opiated stereochemistry can be obtained by conventional methods, for example, by optical resolution of a synthesis intermediate using a chiral acid, such as an optically active amino acid, by example, phenylanaline (see below), which allows the transformation of the compound of formula (II) with retention of the optical isomerism, said optical isomerism being retained until the end of the reaction.
  • the compound of formula (I) is compound (4S) -4 - [[3- [2- (dimethylamino) ethyl) -l / f-indol-5-yl] methyl] -2-oxazolidinone , or Zolmitriptan, useful in the treatment of migraine, cluster headache and headache associated with vascular disorders.
  • the compound of formula (I) is compound 3- [2- (dimethylamino) ethyl)] - 5- (lH-l, 2,4-triazol-l-ylmethyl) indole, or Rizatriptan, useful in the treatment of migraine.
  • the compound of formula (I) is an amine and can form addition salts with organic or inorganic acids when it reacts with the appropriate acids.
  • Said salts include both pharmaceutically acceptable salts and salts that are not pharmaceutically acceptable (ie, pharmaceutically acceptable salts), which, on occasion, may be useful in the synthesis, isolation or purification of the compound of formula (I) desired or the pharmaceutically desired salt.
  • Illustrative, non-limiting examples of such salts include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, acetate, benzoate, citrate, tartrate, fumarate, malate, maleate, lactate, oxalate, succinate, tartrate, mandelate, methanesulfonate, p- toluenesulfonate, although not limited to them.
  • Said salts can be obtained by conventional methods by reacting the compound of formula (I) with the acid in question.
  • said addition salt can be transformed into the corresponding free base by conventional methods, for example, by varying the pH of a solution comprising said salt until the free base is obtained.
  • the compound of formula (I) can be obtained as a free base or salt. In both cases it can be obtained in crystalline form, both as free compounds or as solvates (for example, hydrates, hemidrates, etc.), both forms being included within the scope of the present invention. Solvation methods are generally known in the state of the art. In a particular embodiment, the compound of formula (I) is in the form of its isopropanolate hemidrate.
  • the process of the invention [1] provides compounds of formula (I), their enantiomers, hydrates, solvates and salts.
  • said process provides compounds of formula (I) in which R is 2-oxo-1, 3- oxazolidin-4-yl, as well as their enantiomers or mixtures thereof and their salts (including pharmaceutically acceptable salts and pharmaceutically unacceptable salts).
  • said process provides the compound (4S) -4 - [[3- [2- (dimethylamino) ethyl) -lH-indol-5-yl] methyl] -2-oxazolidinone, or a pharmaceutically acceptable salt of the Zolmitriptan
  • said process provides compounds of formula (I) in which R is 1,2,4-triazol-l-yl, as well as their enantiomers or mixtures thereof and their salts (including pharmaceutically acceptable salts and pharmaceutically unacceptable salts).
  • said process provides the compound 3- [2- (dimethylamino) ethyl)] -5- (lH-1, 2,4-triazol-l-ylmethyl) indole, or a pharmaceutically acceptable salt of Rizatriptan.
  • the compound of formula (VI), the starting product of the process of the invention [1], can be obtained by a process developed in the present invention comprising the synthetic sequence of reactions shown in Reaction Scheme I.
  • the process for obtaining the compound of formula (VI) comprises carrying out a condensation reaction between the aryldiazonium salt formed from the compound of formula (II) [where R has the meaning indicated in relation to the compound of formula (I)] and the monosal alkyl 3 ⁇ (halopropyl) potassium malonate of formula (III) to form the hydrazone of formula (IV).
  • aryldiazonium salt can be carried out by conventional methods (March J., Advanced Organic Chemistry, 4th Ed., 1992, Wiley Interscience, page 526 and pages 635-637), for example, by the reaction of the compound of formula (II) with sodium nitrite and low temperature hydrochloric acid.
  • a condensation reaction occurs between it and a compound with an active methylene, in which at least one of the activating groups is acyl or carboxyl, such as the monosal alkyl 3- (halopropyl) potassium malonate [compound of formula (III) in which R) is a linear or branched Ci-Cs alkyl group, and HaI is halogen], whereby hydrazone formation takes place [compound of formula (IV) in which R , Rj and HaI have the previously mentioned meanings].
  • the invention relates to a compound of formula (IV)
  • R is selected from the group consisting of:
  • X is O, NH, S or CH 2 ,
  • Ri is a linear or branched Ci-Cs alkyl group
  • HaI is halogen
  • the compound of formula (IV) is a compound in which R is 2-oxo-1, 3-oxazolidin-4-yl, Ri is ethyl and HaI is chlorine.
  • the compound of formula (IV) is a compound in which R is 1,2,4-triazol-l-yl, Ri is ethyl and HaI is chlorine.
  • the invention relates to a compound of formula (V)
  • R is selected from the group consisting of:
  • XN JJ where X is O, NH, S or CH 2 , Ri is a linear or branched Cj-Cg alkyl group.
  • the compound of formula (V) is a compound in which R is 2-oxo-1, 3-oxazolidin-4-yl and Ri is ethyl.
  • the Compound of formula (V) is a compound in which R is 1,2,4-triazol-l-yl and Ri is ethyl.
  • the invention relates to a compound of formula (VI)
  • R is selected from the group consisting of:
  • X is O, NH, S or CH 2 .
  • the compound of formula (VI) is a compound in which R is 2-oxo-1, 3-oxazolidin-4-yl. In another particular embodiment, the compound of formula (VI) is a compound in which R is 1,2,4-triazol-l-yl.
  • the compounds of formulas (IV) and (V) can be used to obtain the compounds of formula (I). Therefore, in another aspect, the invention relates to a process, hereinafter process of the invention " 21, for obtaining a tryptamine derivative of formula (I)
  • X is O, NH, S or CH 2 , its enantiomers or mixtures thereof, or its solvates, hydrates or salts, which comprises a) reacting the aryldiazonium salt formed from a compound of formula (II)
  • Ri is a linear or branched Cj-Cs alkyl group, and HaI is halogen, to form the compound of formula (IV)
  • the first stage [step a)] of the process of the invention [2] comprises the previous formation of the aryldiazonium salt from the compound of formula (II) [see Reaction Scheme I].
  • the formation of said aryldiazonium salt can be carried out by conventional methods, for example, by direct introduction of the diazonium group (March J., Advanced Organic Chemistry, 4th Ed., 1992, Wiley Interscience, page 526) or by reaction diazotization with nitrous acid, added or generated in situ (March J., Advanced Organic Chemistry, 4th Ed., 1992, Wiley Interscience, pages 635-637); however, in a particular embodiment, said aryldiazonium salt is obtained by reacting the compound of formula (II) with sodium nitrite and hydrochloric acid at low temperature.
  • a condensation reaction occurs between said aryldiazonium salt and the monosal alkyl 3- (halopropyl) potassium malonate [compound of formula (HI)], whereby the formation of the hydrazone [compound of formula (IV)].
  • This reaction is carried out within a reaction medium that can be aqueous, aqueous alcoholic, etc .; by way of illustration, the reaction medium can be an aqueous alcoholic medium and the alcohol can be an alcohol of five or less carbon atoms, for example, ethanol, etc., although other alcohols can also be used.
  • This reaction it is carried out at a suitable temperature that can vary within a wide range, for example, between O 0 C 4O 0 C, generally at room temperature (typically between 28 0 C and 22 0 C).
  • a suitable temperature typically between O 0 C 4O 0 C, generally at room temperature (typically between 28 0 C and 22 0 C).
  • cyclization of the compound of formula (IV) is produced by a Fisher's delation reaction that yields an indole [compound of formula (v)] from a hydrazone [compound of formula (IV)] in the presence of an appropriate catalyst.
  • the catalyst used is formic acid and the reaction is carried out in an aqueous medium at the reflux temperature, the halogen being replaced by the amino group in the reaction medium itself since during the cyclization process Ammonium formate is released that acts as a source of ammonia to replace the side chain halogen.
  • step c) of the process of the invention [2] hydrolysis of the ester located in position 2 of the indole present in the compound of formula (V) occurs by treatment in an acid medium to obtain the corresponding carboxyl group [compound of formula (VI)].
  • an acid medium to obtain the corresponding carboxyl group [compound of formula (VI)].
  • Virtually any acid, organic or inorganic, capable of hydrolyzing said ester can be used; however, in a particular embodiment, said acid is sulfuric acid in aqueous solution.
  • Steps d) and e) of the process of the invention [2] correspond to steps a) and b) of the process of the invention [1] and have been previously described.
  • the process of the invention [2] provides compounds of formula (I), their enantiomers, hydrates, solvates and salts, which have been previously described.
  • said process provides compounds of formula (I) in which R is 2-oxo-l, 3-oxazolidin-4-yl, as well as their enantiomers or mixtures thereof and their salts (including pharmaceutically salts acceptable and pharmaceutically unacceptable salts).
  • said process provides the compound (4S) -4 - [[3- [2- (dimethylamino) ethyl) -lj and r- indol-5-yl] methyl] -2-oxazolidinone, or a pharmaceutically acceptable salt of Zolmitriptan.
  • said process provides compounds of formula (I) in which R is 1,2,4-triazol-1-yl, as well as their enantiomers or mixtures thereof and their salts (including pharmaceutically acceptable salts and pharmaceutically salts acceptable).
  • said process provides the compound 3- [2- (dimethylamino) ethyl)] - 5- (li : / -l, 2,4-triazol-l-ylmethyl) indole, or a pharmaceutically acceptable salt of Rizatriptan .

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Neurosurgery (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

Le procédé d'obtention de dérivés de la triptamine (I) où R représente un radical d'un hétérocyle, comprend la décarboxylation du dérivé correspondant de l'acide 3-(2-amynoéthyl)-1H-indol carboxylique et la méthylation ultérieure du groupe aminé. Parmi les composés (I), on trouve le zolmitriptan et le rivatriptan, des composés utiles pour le traitement de la migraine.
PCT/ES2006/000465 2005-08-08 2006-08-07 Procede d'obtention de derives de la triptamine Ceased WO2007017546A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES200501995A ES2270717B1 (es) 2005-08-08 2005-08-08 Procedimiento para la obtencion de derivados de triptamina.
ESP200501995 2005-08-08

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WO2007017546A2 true WO2007017546A2 (fr) 2007-02-15
WO2007017546A3 WO2007017546A3 (fr) 2007-04-19

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Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SK278998B6 (sk) * 1991-02-01 1998-05-06 Merck Sharp & Dohme Limited Deriváty imidazolu, triazolu a tetrazolu, spôsob i
NZ253210A (en) * 1992-06-05 1995-09-26 Merck Sharp & Dohme The sulphate salt of 3-(dimethylaminoethyl)-5-(1,2,4-triazol -1-ylmethyl) indole and medicaments
ES2204302B2 (es) * 2002-08-07 2005-03-01 Laboratorios Vita, S.A. Procedimiento para la obtencion de un compuesto farmaceuticamente activo.

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WO2007017546A3 (fr) 2007-04-19
ES2270717B1 (es) 2008-03-01

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