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WO2007017546A2 - Method of obtaining tryptamine derivatives - Google Patents

Method of obtaining tryptamine derivatives 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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Prior art keywords
formula
compound
ethyl
reaction
vii
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PCT/ES2006/000465
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Spanish (es)
French (fr)
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WO2007017546A3 (en
Inventor
José Vicente Murillo Garrido
Jorge MARTÍN JUÁREZ
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Ragactives SL
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Ragactives SL
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    • 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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Abstract

The invention relates to a method of obtaining tryptamine derivatives (I), wherein R is a radical of a heterocycle, comprising the decarboxylation of the corresponding derivative of 3-(2-aminoethyl)-1H-indole carboxylic acid and the subsequent methylation of the amino group. Compounds (I) include zolmitriptan and rizatriptan which can be used for the treatment of migraines.

Description

PROCEDIMIENTO PARA LA OBTENCIÓN DE DERIVADOS DE PROCEDURE FOR OBTAINING DERIVATIVES OF

TRIPTAMINATRIPTAMINE

CAMPO DE LA INVENCIÓN La invención se refiere a un procedimiento para la obtención de derivados de triptamina, sus solvatos, hidratos o sus sales farmacéuticamente aceptables, así como a algunos de los intermedios de dicho procedimiento.FIELD OF THE INVENTION 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.

ANTECEDENTES DE LA INVENCIÓN Los derivados de triptamina, entre los que se encuentra el Zolmitriptán, denominación común internacional del compuesto (4S)-4-[[3-[2-(dimetilamino)etil)- lH-indol-5-il]metil]-2-oxazolidinona, y el Rizatriptán, denominación común internacional del compuesto 3-[2-(dimetilamino)etil)]-5-(l//-l,2,4-triazol-l-ilmetil) indol, son productos con una excepcional actividad agonista por los receptores similares al 5-HTi, además de presentar una excelente absorción tras la administración oral. Estos compuestos han demostrado ser particularmente útiles en el tratamiento de la migraña, cefalea en racimos y cefalea asociada con trastornos vasculares.BACKGROUND OF THE INVENTION 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.

El Zolmitriptán y otros derivados de triptamina fueron descritos por primera vez en la solicitud de patente internacional WO 91/18897, mientras que el Rizatriptán fue descrito por primera vez en la solicitud de patente europea EP 497512. En dicha solicitud de patente WO 91/18897, se describe la obtención de Zolmitriptán mediante reacción de delación de Fisher del compuesto obtenido al condensar la correspondiente fenilhidracina con un aldehido. No obstante, este procedimiento presenta numerosos inconvenientes. El proceso en su conjunto transcurre con solo un 18% de rendimiento y el producto final requiere una etapa de purificación por columna. Algunos de los reactivos empleados, tales como el cloruro de estaño, son tóxicos e intermedios como la hidracina son potencialmente cancerígenos. Todo ello provoca que el procedimiento total sea poco productivo.Zolmitriptan and other tryptamine derivatives were first described in international patent application WO 91/18897, while Rizatriptan was first described in European patent application EP 497512. In said patent application WO 91/18897 , the preparation of Zolmitriptan by Fisher's delation reaction of the compound obtained by condensing the corresponding phenylhydrazine with an aldehyde is described. However, this procedure has numerous drawbacks. The whole process takes place with only 18% yield and the final product requires a stage of purification per column. Some of the reagents used, such as tin chloride, are toxic and intermediate such as hydrazine are potentially carcinogenic. All this causes the total procedure to be unproductive.

Un procedimiento alternativo para la obtención de Zolmitriptán, que supera alguno de los inconvenientes expuestos anteriormente, se describe en EP 0 843 672. Dicho procedimiento comprende una preparación optimizada del intermedio (4S)-4-(4- aminobencil)-l,3-oxazolidinona en un proceso "one-pot" y la obtención de Zolmitriptán en base a ese intermedio en un segundo proceso "one-pot" que incluye la formación de la sal de diazonio de dicho intermedio seguido por la reacción de Fisher (por adición de la 4,4-dietoxi-N,N-dimetilbutilamina). No obstante, este procedimiento no es aplicable a escala industrial debido al elevado contenido de impurezas como consecuencia de la realización de la reacción "one-pot" y al bajo rendimiento obtenido (del orden del 30%). En una solicitud de patente internacional más reciente (WO 2004/014901) se describe otra aproximación sintética para la obtención de Zolmitriptán mediante una ruta que comprende numerosas etapas y que obliga al aislamiento de un gran número de intermedios provocando que dicho procedimiento se alargue en exceso. El proceso se basa, además, en la reacción de Fisher que requiere la utilización de hidracina (potencialmente cancerígena) como intermedio de síntesis.An alternative procedure for obtaining Zolmitriptan, which overcomes some of the drawbacks set forth above, is described in EP 0 843 672. Said process comprises an optimized preparation of intermediate (4S) -4- (4- aminobenzyl) -l, 3- oxazolidinone in a "one-pot" process and obtaining Zolmitriptan based on that intermediate in a second "one-pot" process that includes the formation of the diazonium salt of said intermediate followed by the Fisher reaction (by the addition of 4,4-diethoxy-N, N-dimethylbutylamine). However, this procedure is not applicable on an industrial scale due to the high impurity content as a result of the "one-pot" reaction and the low yield obtained (of the order of 30%). In a more recent international patent application (WO 2004/014901) another synthetic approach is described for obtaining Zolmitriptan by means of a route that comprises numerous stages and that obliges the isolation of a large number of intermediates causing said procedure to be excessively lengthened. . The process is also based on the Fisher reaction that requires the use of hydrazine (potentially carcinogenic) as a synthesis intermediate.

Existen, por tanto, en las síntesis conocidas de Zolmitriptán y derivados problemas asociados con el uso de determinados reactivos (cuyo manejo resulta peligroso) y con la realización de una reacción de Fisher que requiere el empleo de hidracina como intermedio. Por otra parte, se detectan bajos rendimientos en algunas partes de los procesos citados y las rutas sintéticas son excesivamente largas. Por tanto, sería conveniente desarrollar un procedimiento alternativo que elimine la totalidad o parte de dichos problemas, y que, además, sea susceptible de aplicación a escala industrial y proporcione un producto con buen rendimiento y calidad.There are, therefore, in the known synthesis of Zolmitriptan and derived problems associated with the use of certain reagents (whose handling is dangerous) and with the performance of a Fisher reaction that requires the use of hydrazine as an intermediate. On the other hand, low yields are detected in some parts of the processes mentioned and the synthetic routes are excessively long. Therefore, it would be convenient to develop an alternative procedure that eliminates all or part of these problems, and that, in addition, is capable of being applied on an industrial scale and provides a product with good performance and quality.

COMPENDIO DE LA INVENCIÓNSUMMARY OF THE INVENTION

Ahora se ha encontrado una ruta sintética alternativa para la obtención de derivados de triptamina de fórmula (I), en concreto derivados de 3-(2-dimetilaminoetil)- lH-indol sustituidos en la posición 5, que superan la totalidad o parte de los problemas previamente mencionados. Sorprendentemente y, a diferencia de lo expuesto en el estado de la técnica, partiendo de un derivado de indol carboxilado es posible llegar al correspondiente derivado de triptamina mediante una reacción de descarboxilación seguida de una metilación del grupo amino.An alternative synthetic route has now been found for obtaining tryptamine derivatives of formula (I), namely 3- (2-dimethylaminoethyl) -lH-indole derivatives substituted at position 5, which exceed all or part of the previously mentioned problems. Surprisingly and, unlike what is stated in the prior art, starting from a carboxylated indole derivative it is possible to reach the corresponding triptamine derivative by a decarboxylation reaction followed by methylation of the amino group.

Por tanto, en un aspecto, la invención se relaciona con un procedimiento para la obtención de un derivado de triptamina de fórmula (I) (definido más adelante) que comprende la descarboxilación de un compuesto de fórmula (VI) (definido más adelante) y posterior aminometilación del intermedio obtenido. En otros aspectos, la invención se relaciona con un compuesto de fórmula (IV) (definido más adelante), un compuesto de fórmula (V) (definido más adelante) y un compuesto de fórmula (VI) (definido más adelante). Dichos compuestos de fórmula (IV), (V) y (VI) pueden ser utilizados en la síntesis de los compuestos de fórmula (I). En otro aspecto, la invención se relaciona con un procedimiento para la obtención de derivados de triptamina de fórmula (I) que comprende el empleo de dichos compuestos de fórmula (IV), (V) y (VI).Therefore, in one aspect, 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. In other aspects, 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). In another aspect, 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).

DESCRIPCIÓN DETALLADA DE LA INVENCIÓN En un aspecto, la invención se relaciona con un procedimiento, en adelante procedimiento de la invención [1], para la obtención de un derivado de triptamina de fórmula (I)DETAILED DESCRIPTION OF THE INVENTION In one aspect, the invention relates to a process, hereinafter process of the invention [1], for obtaining a tryptamine derivative of formula (I)

Figure imgf000004_0001
Figure imgf000004_0001

(D donde R se selecciona del grupo formado por:(D where R is selected from the group consisting of:

Figure imgf000004_0002
en donde X es O, NH, S o CH2, sus enantiómeros o mezclas de los mismos, o sus solvatos, hidratos o sales, que comprende a) descarboxilar un compuesto de fórmula (VI)
Figure imgf000004_0002
wherein 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)

Figure imgf000004_0003
Figure imgf000004_0003

(VI) donde R tiene el significado previamente indicado, para obtener un compuesto de fórmula (VII)

Figure imgf000005_0001
(VI) where R has the previously indicated meaning, to obtain a compound of formula (VII)
Figure imgf000005_0001

(VII) donde R tiene el significado previamente indicado, y b) someter dicho compuesto de fórmula (VII) a una reacción de aminometilación para obtener el compuesto de fórmula (I).(VII) where R has the previously indicated meaning, and b) subjecting said compound of formula (VII) to an aminomethylation reaction to obtain the compound of formula (I).

La primera etapa [etapa a)] del procedimiento de la invención [1] consiste en la descarboxilación del grupo ácido carboxílico ubicado en la posición 2 del indol [compuesto de fórmula (VI)]. Dicha reacción de descarboxilación puede llevarse a cabo por cualquier método convencional, por ejemplo, mediante tratamiento con un ácido, ventajosamente, un ácido fuerte. Prácticamente cualquier ácido, orgánico o inorgánico, preferentemente, inorgánico, fuerte, puede ser utilizado, por ejemplo, ácido sulfúrico, etc. Alternativamente, esta reacción puede realizarse utilizando una mezcla de ácidos apropiados. Para llevar a cabo esta reacción, el compuesto de fórmula (VI) estará, en general, disuelto o suspendido en un medio de reacción que comprende dicho ácido, por ejemplo, una disolución acuosa de ácido sulfúrico, aunque pueden utilizarse otros medios y ácidos siempre y cuando resulten apropiados. La reacción de descarboxilación puede llevarse a cabo a una temperatura comprendida dentro de un amplio intervalo, por ejemplo, a una temperatura comprendida entre la temperatura ambiente (típicamente entre 180C y 220C) y la temperatura de reflujo. En una realización particular, la descarboxilación del compuesto de fórmula (VI) se lleva a cabo mediante el tratamiento del compuesto de fórmula (VI) con ácido sulfúrico, en disolución acuosa, a la temperatura de reflujo.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. Virtually any acid, organic or inorganic, preferably inorganic, strong, can be used, for example, sulfuric acid, etc. Alternatively, this reaction can be performed using a mixture of appropriate acids. To carry out this reaction, 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. and when appropriate. 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. In a particular embodiment, 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.

El compuesto de fórmula (VI) puede obtenerse a partir de un compuesto de fórmula (II) por reacción con un compuesto de fórmula (III) a través de los intermedios de fórmulas (IV) y (V), tal como se muestra en el Esquema de Reacción I y se describe más adelante.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.

La segunda etapa [etapa b)] del procedimiento de la invención [1] consiste en una metilación del grupo amino (-NH2). Dicha aminometilación se puede realizar por cualquiera de los métodos conocidos por un experto en la materia, por ejemplo, mediante reacción con un haluro de metilo o, preferentemente, por metilación reductora. En una realización particular, esta etapa de aminometilación se lleva a cabo mediante metilación reductora haciendo reaccionar el compuesto de fórmula (VII) con formaldehído en presencia de un agente reductor y un ácido, tal como se muestra a continuación: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. In a particular embodiment, 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:

HCHO/reductorHCHO / reducer

Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0001
Figure imgf000006_0002

(VII) (I)(VII) (I)

[donde R tiene los significados indicados previamente][where R has the meanings indicated previously]

Prácticamente cualquier agente reductor apropiado puede ser utilizado; no obstante, en una realización particular, como agente reductor puede emplearse, entre otros, un hidruro, tal como cianoborohidruro sódico, borohidruro sódico junto con Ti(OiPr)4, etc. Como ácido puede emplearse cualquier ácido apropiado, por ejemplo, un ácido orgánico tal como ácido fórmico, acético, etc. La reacción de metilación reductora se lleva a cabo en el seno de un disolvente. Prácticamente cualquier disolvente en el que el compuesto de fórmula (VII) sea soluble o dispersable puede ser utilizado; a modo ilustrativo, no limitativo, pueden utilizarse alcoholes y disolventes miscibles con el agua, tales como tetrahidrofurano, dimetilformamida, etc., preferentemente alcoholes; en una realización particular, el disolvente es un alcohol, por ejemplo, un alcohol de cinco o menos átomos de carbono, por ejemplo, metanol, etc., aunque también pueden utilizarse otros alcoholes. Esta reacción de metilación reductora puede llevarse a cabo a una temperatura comprendida dentro de un amplio intervalo, por ejemplo, a una temperatura comprendida entre -1O0C y +5O0C, preferentemente, entre 15°C y 4O0C, más preferentemente, entre 2O0C y 3O0C. En una realización particular, esta reacción de metilación reductora se lleva a cabo mediante el tratamiento del compuesto de fórmula (VII) en metanol con formaldehído acuoso, cianoborohidruro sódico y ácido acético.Virtually 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. As 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. Virtually 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; In a particular embodiment, 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. In a particular embodiment, this reductive methylation reaction is carried out by treating the compound of formula (VII) in methanol with aqueous formaldehyde, sodium cyanoborohydride and acetic acid.

En otra realización particular, esta etapa de aminometilación [etapa b)] se lleva a cabo mediante una reacción de metilación haciendo reaccionar el compuesto de fórmula (VII) con un haluro de metilo, tal como bromuro de metilo, yoduro de metilo, etc. Esta reacción de metilación se lleva a cabo en el seno de un disolvente. Prácticamente cualquier disolvente en el que el compuesto de fórmula (VII) sea soluble o dispersable puede ser utilizado; a modo ilustrativo, no limitativo, pueden utilizarse tetrahidrofurano, dimetilformamida, alcoholes, etc. Esta reacción de metilación puede llevarse a cabo a una temperatura comprendida dentro de un amplio intervalo, por ejemplo, a una temperatura comprendida entre -100C y +5O0C, preferentemente, entre 00C y 4O0C, más preferentemente, entre 150C y 25°C.In another particular embodiment, 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. This methylation reaction is carried out in a solvent. Practically 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.

El compuesto de fórmula (I) tiene un carbono quiral y, por tanto, existe bien en forma de sus enantiómeros (R) o (S) aislados o bien en forma de mezclas de dichos enantiómeros. Tal como se utiliza en esta descripción el término "mezclas de enantiómeros" o "mezclas enantioméricas" incluye tanto las mezclas racémicas como las mezclas enriquecidas en uno cualquiera de los enantiómeros. Los enantiómeros (R) y (S) del compuesto de fórmula (I) obtenidos pueden separarse por métodos convencionales de resolución de mezclas de enantiómeros, por ejemplo, mediante cristalización fraccionada, métodos cromatográficos, etc. Brevemente, la resolución de la mezcla de enantiómeros puede realizarse por cualquier método convencional, por ejemplo, utilizando columnas cromatográficas quirales o bien mediante cristalización fraccionada de sales de los enantiómeros correspondiente con los ácidos ópticamente activos (quirales) apropiados; en este caso, la sal correspondiente al enantiómero deseado se puede recristalizar las veces necesarias hasta obtener el enantiómero deseado con la pureza deseada.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. As used herein, 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. Briefly, 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.

En una realización particular, el compuesto de fórmula (I) obtenido mediante el procedimiento proporcionado por esta invención se obtiene en forma de una mezcla de enantiómeros, por ejemplo, en forma de una mezcla racémica. Por tanto, si se desea, la mezcla de enantiómeros obtenida puede resolverse en sus enantiómeros correspondientes para obtener el enantiómero deseado. En una realización particular, dicho enantiómero es el enantiómero (S).In a particular embodiment, 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. In a particular embodiment, said enantiomer is the enantiomer (S).

Alternativamente, el enantiómero deseado del compuesto de fórmula (I) puede obtenerse mediante una síntesis enantioselectiva, a partir del producto de partida [compuesto de fórmula (VI)] con la esteroquímica apropiada, mediante un procedimiento que conserva la isometría óptica hasta el final. El producto de partida con la estereoquímica api'opiada, tal como se menciona más adelante, puede obtenerse por métodos convencionales, por ejemplo, mediante resolución óptica de un intermedio de síntesis utilizando un ácido quiral, tal como un aminoácido ópticamente activo, por ejemplo, fenilanalina (véase más adelante), que permite la transformación del compuesto de fórmula (II) con retención de la isomería óptica, conservándose dicha isomería óptica hasta el final de la reacción.Alternatively, 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, as mentioned below, 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.

En una realización particular, el compuesto de fórmula (I) es el compuesto (4S)- 4-[[3-[2-(dimetilamino)etil)-l/f-indol-5-il]metil]-2-oxazolidinona, o Zolmitriptán, útil en el tratamiento de la migraña, la cefalea en racimos y la cefalea asociada con trastornos vasculares. En otra realización particular, el compuesto de fórmula (I) es el compuesto 3-[2-(dimetilamino)etil)]-5-(lH-l,2,4-tríazol-l-ilmetil) indol, o Rizatriptán, útil en el tratamiento de la migraña. El compuesto de fórmula (I) es una amina y puede formar sales de adición con ácidos orgánicos o inorgánicos cuando reacciona con los ácidos apropiados. Dichas sales incluyen tanto sales farmacéuticamente aceptables como sales que no sean famacéuticamente aceptables (es decir, sales farmacéuticamente no aceptables), las cuales, en ocasiones, pueden ser útiles en la síntesis, aislamiento o purificación del compuesto de fórmula (I) deseado o de la sal farmacéuticamente deseada. Ejemplos ilustrativos, no limitativos, de dichas sales incluyen hidrocloruro, hidrobromuro, hidroyoduro, sulfato, fosfato, nitrato, acetato, benzoato, citrato, tartrato, fumarato, malato, maleato, lactato, oxalato, succinato, tartrato, mandelato, metansulfonato, p- toluensulfonato, aunque no se limitan a ellas. Dichas sales pueden obtenerse por métodos convencionales haciendo reaccionar el compuesto de fórmula (I) con el ácido en cuestión. Opcionalmente, si se desea, dicha sal de adición puede ser transformada en la correspondiente base libre por métodos convencionales, por ejemplo, variando el pH de una disolución que comprende dicha sal hasta obtener la base libre.In a particular embodiment, 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. In another particular embodiment, 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. Optionally, if desired, 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.

El compuesto de fórmula (I) se puede obtener en forma de base libre o de sal. En ambos casos se puede obtener en forma cristalina, tanto como compuestos libres o como solvatos (por ejemplo, hidratos, hemidratos, etc.) quedando ambas formas incluidas dentro del ámbito de la presente invención. Los métodos de solvatación son generalmente conocidos en el estado de la técnica. En una realización particular, el compuesto de fórmula (I) se encuentra en la forma de su isopropanolato hemidrato. El procedimiento de la invención [1] proporciona compuestos de fórmula (I), sus enantiómeros, hidratos, solvatos y sales. En una realización particular, dicho procedimiento proporciona compuestos de fórmula (I) en los que R es 2-oxo-l,3- oxazolidin-4-ilo, así como sus enantiómeros o mezclas de los mismos y sus sales (incluyendo las sales farmacéuticamente aceptables y las sales farmacéuticamente no aceptables). En una realización particular, dicho procedimiento proporciona el compuesto (4S)-4-[[3-[2-(dimetilamino)etil)-lH-indol-5-il]metil]-2-oxazolidinona, o una sal farmacéuticamente aceptable del Zolmitriptán. El radical 2-oxo-l,3-oxazolidin-4-ilo de fórmulaThe 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. In a particular embodiment, 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). In a particular embodiment, 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 The 2-oxo-1, 3-oxazolidin-4-yl radical of the formula

Figure imgf000009_0001
Figure imgf000009_0001

En otra realización particular, dicho procedimiento proporciona compuestos de fórmula (I) en los que R es 1,2,4-triazol-l-ilo, así como sus enanti omeros o mezclas de los mismos y sus sales (incluyendo las sales farmacéuticamente aceptables y las sales farmacéuticamente no aceptables). En una realización particular, dicho procedimiento proporciona el compuesto 3-[2-(dimetilamino)etil)]-5-(lH-l,2,4-triazol-l-ilmetil)indol, o una sal farmacéuticamente aceptable del Rizatriptán.In another particular embodiment, 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). In a particular embodiment, 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.

El compuesto de fórmula (VI), producto de partida del procedimiento de la invención [1], puede ser obtenido mediante un procedimiento desarrollado en la presente invención que comprende la secuencia sintética de reacciones que se muestra en el Esquema de Reacción I.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.

Esquema de Reacción IReaction Scheme I

Figure imgf000009_0002
En dicho Esquema de Reacción I, R, R, y HaI tienen los significados mencionados en la descripción. Estas etapas se describirán detalladamente a continuación. Como puede apreciarse en dicho Esquema de Reacción I, el procedimiento de obtención del compuesto de fórmula (VI) comprende la realización de una reacción de condensación entre la sal de arildiazonio formada a partir del compuesto de fórmula (II) [donde R tiene el significado indicado en relación con el compuesto de fórmula (I)] y la monosal alquil 3~(halopropil)malonato potásico de fórmula (III) para formar la hidrazona de fórmula (IV). La formación de dicha sal de arildiazonio puede llevarse a cabo por métodos convencionales (March J., Advanced Organic Chemistry, 4th Ed., 1992, Wiley Interscience, página 526 y páginas 635-637), por ejemplo, mediante la reacción del compuesto de fórmula (II) con nitrito sódico y ácido clorhídrico a baja temperatura. Una vez formada dicha sal de arildiazonio tiene lugar una reacción de condensación entre ésta y un compuesto con un metileno activo, en el que al menos uno de los grupos activantes es acilo o carboxilo, tal como la monosal alquil 3- (halopropil)malonato potásico [compuesto de fórmula (III) en el que R) es un grupo alquilo Ci-Cs lineal o ramificado, y HaI es halógeno], con lo que tiene lugar la formación de la hidrazona [compuesto de fórmula (IV) en el que R, Rj y HaI tienen los significados previamente mencionados].
Figure imgf000009_0002
In said Reaction Scheme I, R, R, and HaI have the meanings mentioned in the description. These steps will be described in detail below. As can be seen in said 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). The formation of said 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. Once said aryldiazonium salt has formed, 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].

El paso del compuesto de fórmula (IV) al compuesto de fórmula (V) [en el que R y Ri tienen los significados previamente mencionados] corresponde a una ciclación similar a la conocida como ciclación de Fisher donde se obtiene un indol a partir de una hidrazona en presencia de un catalizador. En una realización particular el catalizador empleado es ácido fórmico y la reacción se lleva a cabo en medio acuoso a la temperatura de reflujo. La sustitución del halógeno por el grupo amino se realiza en el medio de la reacción, ya que en el proceso de ciclación se libera formiato amónico que actúa de fuente de amoníaco para sustituir al halógeno de la cadena lateral. Por último, se hidroliza el éster ubicado en la posición 2 del indol presente en el compuesto de fórmula (V) mediante tratamiento en medio ácido para obtener el grupo carboxilo correspondiente [compuesto de fórmula (VI)].The passage of the compound of formula (IV) to the compound of formula (V) [in which R and Ri have the aforementioned meanings] corresponds to a cyclization similar to that known as Fisher's cyclization where an indole is obtained from a Hydrazone in the presence of a catalyst. In a particular embodiment the catalyst employed is formic acid and the reaction is carried out in aqueous medium at reflux temperature. The replacement of the halogen by the amino group is carried out in the middle of the reaction, since in the cyclization process ammonium formate is released that acts as a source of ammonia to replace the halogen of the side chain. Finally, the ester located in position 2 of the indole present in the compound of formula (V) is hydrolyzed by treatment in an acid medium to obtain the corresponding carboxyl group [compound of formula (VI)].

Los compuestos de fórmula (IV), (V) y (VI), que pueden ser utilizados en la síntesis de los compuestos de fórmula (I) constituyen aspectos adicionales de esta invención.The compounds of formula (IV), (V) and (VI), which can be used in the synthesis of the compounds of formula (I) constitute additional aspects of this invention.

Por tanto, en otro aspecto, la invención se relaciona con un compuesto de fórmula (IV)

Figure imgf000011_0001
Therefore, in another aspect, the invention relates to a compound of formula (IV)
Figure imgf000011_0001

(IV) donde(IV) where

R se selecciona del grupo formado por:R is selected from the group consisting of:

H N. O < NH N. O <N

XX

en donde X es O, NH, S o CH2,where X is O, NH, S or CH 2 ,

Ri es un grupo alquilo Ci-Cs lineal o ramificado, yRi is a linear or branched Ci-Cs alkyl group, and

HaI es halógeno.HaI is halogen.

En una realización particular, el compuesto de fórmula (IV) es un compuesto en el que R es 2-oxo-l,3-oxazolidin-4-ilo, Ri es etilo y HaI es cloro. En otra realización particular, el compuesto de fórmula (IV) es un compuesto en el que R es 1,2,4-triazol-l- ilo, Ri es etilo y HaI es cloro.In a particular embodiment, 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. In another particular embodiment, 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.

En otro aspecto, la invención se relaciona con un compuesto de fórmula (V)In another aspect, the invention relates to a compound of formula (V)

Figure imgf000011_0002
donde
Figure imgf000011_0002
where

R se selecciona del grupo formado por:R is selected from the group consisting of:

H .N. O N.H .N. O N.

^N ^ N

X N JJ en donde X es O, NH, S o CH2, Ri es un grupo alquilo Cj-Cg lineal o ramificado.XN JJ where X is O, NH, S or CH 2 , Ri is a linear or branched Cj-Cg alkyl group.

En una realización particular, el compuesto de fórmula (V) es un compuesto en el que R es 2-oxo-l,3-oxazolidin-4-ilo y Ri es etilo. En otra realización particular, el compuesto de fórmula (V) es un compuesto en el que R es 1,2,4-triazol-l-ilo y Ri es etilo.In a particular embodiment, the compound of formula (V) is a compound in which R is 2-oxo-1, 3-oxazolidin-4-yl and Ri is ethyl. In another particular embodiment, the Compound of formula (V) is a compound in which R is 1,2,4-triazol-l-yl and Ri is ethyl.

En otro aspecto, la invención se relaciona con un compuesto de fórmula (VI)In another aspect, the invention relates to a compound of formula (VI)

Figure imgf000012_0001
Figure imgf000012_0001

(VI) donde(VI) where

R se selecciona del grupo formado por:R is selected from the group consisting of:

Figure imgf000012_0002
en donde X es O, NH, S o CH2.
Figure imgf000012_0002
where X is O, NH, S or CH 2 .

En una realización particular, el compuesto de fórmula (VI) es un compuesto en el que R es 2-oxo-l,3-oxazolidin-4-ilo. En otra realización particular, el compuesto de fórmula (VI) es un compuesto en el que R es 1,2,4-triazol-l-ilo.In a particular embodiment, 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.

Los compuestos de fórmulas (IV) y (V) pueden ser utilizados para la obtención de los compuestos de fórmula (I). Por tanto, en otro aspecto, la invención se relaciona con un procedimiento, en adelante procedimiento de la invención ¡"21, para la obtención de un derivado de triptamina de fórmula (I)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)

Figure imgf000012_0003
Figure imgf000012_0003

(D donde R se selecciona del grupo formado por:(D where R is selected from the group consisting of:

Figure imgf000012_0004
en donde X es O, NH, S o CH2, sus enantiómeros o mezclas de los mismos, o sus solvatos, hidratos o sales, que comprende a) hacer reaccionar la sal de arildiazonio formada a partir de un compuesto de fórmula (II)
Figure imgf000012_0004
wherein 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)

Figure imgf000013_0001
Figure imgf000013_0001

(II) donde R tiene el significado previamente mencionado; con la monosal alquil 3-(halopropil)malonato potásico de fórmula (III)(II) where R has the previously mentioned meaning; with the monosal alkyl 3- (halopropyl) potassium malonate of formula (III)

Figure imgf000013_0002
donde
Figure imgf000013_0002
where

Ri es un grupo alquilo Cj-Cs lineal o ramificado, y HaI es halógeno, para formar el compuesto de fórmula (IV)Ri is a linear or branched Cj-Cs alkyl group, and HaI is halogen, to form the compound of formula (IV)

Figure imgf000013_0003
Figure imgf000013_0003

(IV) donde R, Ri y HaI tienen los significados previamente indicados; b) someter el compuesto de fórmula (IV) a una reacción de delación de Fisher para formar un compuesto de fórmula (V)(IV) where R, Ri and HaI have the previously indicated meanings; b) subjecting the compound of formula (IV) to a Fisher's delation reaction to form a compound of formula (V)

Figure imgf000013_0004
donde R y Ri tienen los significados previamente indicados; c) hidrolizar el grupo éster del compuesto de fórmula (V) para obtener el compuesto de fórmula (VI)
Figure imgf000014_0001
Figure imgf000013_0004
where R and Ri have the meanings previously indicated; c) hydrolyzing the ester group of the compound of formula (V) to obtain the compound of formula (VI)
Figure imgf000014_0001

(VI) donde R tiene el significado previamente indicado; d) descarboxilar dicho compuesto de fórmula (VI) para obtener un compuesto de fórmula (VII)(VI) where R has the previously indicated meaning; d) decarboxylating said compound of formula (VI) to obtain a compound of formula (VII)

Figure imgf000014_0002
Figure imgf000014_0002

(VII) donde R tiene el significado previamente indicado, y e) someter dicho compuesto de fórmula (VII) a una reacción de aminometil ación para obtener el compuesto de fórmula (I).(VII) where R has the previously indicated meaning, and e) subjecting said compound of formula (VII) to an aminomethyl reaction to obtain the compound of formula (I).

La primera etapa [etapa a)] del procedimiento de la invención [2] comprende la formación previa de la sal de arildiazonio a partir del compuesto de fórmula (II) [véase el Esquema de Reacción I]. La formación de dicha sal de arildiazonio puede llevarse a cabo mediante métodos convencionales, por ejemplo, mediante introducción directa del grupo diazonio (March J., Advanced Organic Chemistry, 4th Ed., 1992, Wiley Interscience, página 526) o mediante diazotación por reacción con ácido nitroso, añadido o generado in situ (March J., Advanced Organic Chemistry, 4th Ed., 1992, Wiley Interscience, páginas 635-637); no obstante, en una realización particular, dicha sal de arildiazonio se obtiene haciendo reaccionar el compuesto de fórmula (II) con nitrito sódico y ácido clorhídrico a baja temperatura. Una vez formada la sal de arildiazonio se produce una reacción de condensación entre dicha sal de arildiazonio y la monosal alquil 3-(halopropil)malonato potásico [compuesto de fórmula (HI)], con lo que tiene lugar la formación de la hidrazona [compuesto de fórmula (IV)]. Esta reacción se lleva a cabo en el seno de un medio de reacción que puede ser acuoso, acuo- alcohólico, etc.; a modo ilustrativo, el medio de reacción puede ser un medio acuo- alcohólico y el alcohol puede ser un alcohol de cinco o menos átomos de carbono, por ejemplo, etanol, etc., aunque también se pueden utilizar otros alcoholes. Esta reacción se lleva a cabo a una temperatura adecuada que puede variar dentro de un amplio intervalo, por ejemplo, entre O0C 4O0C, generalmente a temperatura ambiente (típicamente entre 280C y 220C). En el Ejemplo 1 se describe una forma particular de obtener el compuesto de fórmula (IV). En la segunda etapa [etapa b)] del procedimiento de la invención [2] se produce la ciclación del compuesto de fórmula (IV) mediante una reacción de delación de Fisher que rinde un indol [compuesto de fórmula (v)] a partir de una hidrazona [compuesto de fórmula (IV)] en presencia de un catalizador apropiado. En una realización particular el catalizador empleado es ácido fórmico y la reacción se lleva a cabo en un medio acuoso a la temperatura de reflujo, produciéndose la sustitución del halógeno por el grupo amino en el propio medio de la reacción ya que durante el proceso de ciclación se libera formiato amónico que actúa de fuente de amoníaco para sustituir al halógeno de la cadena lateral.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. Once the aryldiazonium salt is formed, 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). In Example 1 a particular way of obtaining the compound of formula (IV) is described. In the second stage [step b)] of the process of the invention [2] 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. In a particular embodiment 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.

En la tercera etapa [etapa c)] del procedimiento de la invención [2] se produce la hidrólisis del éster ubicado en la posición 2 del indol presente en el compuesto de fórmula (V) mediante tratamiento en medio ácido para obtener el grupo carboxilo correspondiente [compuesto de fórmula (VI)]. Prácticamente cualquier ácido, orgánico o inorgánico, capaz de hidrolizar dicho éster puede ser utilizado; no obstante, en una realización particular, dicho ácido es ácido sulfúrico en disolución acuosa. Las etapas d) y e) del procedimiento de la invención [2] corresponden a las etapas a) y b) del procedimiento de la invención [1] y han sido descritas previamente.In the third stage [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)]. 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.

Al igual que el procedimiento de la invención [1], el procedimiento de la invención [2] proporciona compuestos de fórmula (I), sus enantiómeros, hidratos, solvatos y sales, los cuales han sido descritos previamente. En una realización particular, dicho procedimiento proporciona compuestos de fórmula (I) en los que R es 2-oxo-l,3-oxazolidin-4-ilo, así como sus enantiómeros o mezclas de los mismos y sus sales (incluyendo las sales farmacéuticamente aceptables y las sales farmacéuticamente no aceptables). En una realización particular, dicho procedimiento proporciona el compuesto (4S)-4-[[3-[2-(dimetilamino)etil)-ljyr-indol-5-il]metil]-2-oxazolidinona, o una sal farmacéuticamente aceptable del Zolmitriptán. En otra realización particular, dicho procedimiento proporciona compuestos de fórmula (I) en los que R es 1,2,4- triazol-1-ilo, así como sus enantiómeros o mezclas de los mismos y sus sales (incluyendo las sales farmacéuticamente aceptables y las sales farmacéuticamente no aceptables). En una realización particular, dicho procedimiento proporciona el compuesto 3-[2-(dimetilamino)etil)]-5-(li:/-l,2,4-triazol-l-ilmetil)indol, o una sal farmacéuticamente aceptable del Rizatriptán.Like the process of the invention [1], the process of the invention [2] provides compounds of formula (I), their enantiomers, hydrates, solvates and salts, which have been previously described. In a particular embodiment, 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). In a particular embodiment, 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. In another particular embodiment, 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). In a particular embodiment, 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 .

Los siguientes ejemplos ilustran distintas realizaciones de la invención y no deben ser considerados limitativos del alcance de la misma.The following examples illustrate different embodiments of the invention and should not be considered as limiting the scope thereof.

EJEMPLO 1EXAMPLE 1

Síntesis de etiI-5-cloro-2-[[(S)-4-((l,3-oxazoIidin-2-ona)iImetiI)fenillhidrazin-2- ilidenolpentanoato [compuesto de fórmula (IV)I Se añadió lentamente una disolución de 6,3 g (91 mmoles) de nitrito sódico enSynthesis of etiI-5-chloro-2 - [[(S) -4 - ((l, 3-oxazoIidin-2-one) iImetiI) phenylhydrazin-2- ylideneolpentanoate [compound of formula (IV) I] A solution was slowly added of 6.3 g (91 mmol) of sodium nitrite in

12 mL de agua a una disolución de (S)-4-(4-aminobencil)-l,3-oxazolidin-2-ona hidrocloruro (76 mmoles) en 95 mL de agua y 15 mL de ácido clorhídrico concentrado, manteniendo la temperatura de reacción por debajo de O0C. La mezcla de reacción se mantuvo durante 15 minutos a esa temperatura. Después de ese intervalo de tiempo, se añadió sobre la mezcla de reacción una disolución previamente preparada de etil-3- (cloropropil)malonato potásico (153 mmoles) en 180 mL de etanol. Finalizada la adición, se ajustó el pH a 4,5, se aumentó la temperatura hasta temperatura ambiente y se mantuvo esa temperatura hasta el final de la reacción. Completada la reacción, se reajustó el pH a 6,5, se destiló a vacío el etanol y se extrajo con 300 mL de cloruro de metileno. La fase orgánica se destiló a vacío para obtener 43 g de un aceite correspondiente al producto del título que se usó directamente en el paso siguiente.12 mL of water to a solution of (S) -4- (4-aminobenzyl) -l, 3-oxazolidin-2-one hydrochloride (76 mmol) in 95 mL of water and 15 mL of concentrated hydrochloric acid, maintaining the temperature Reaction below O 0 C. The reaction mixture was maintained for 15 minutes at that temperature. After that time interval, a previously prepared solution of ethyl-3- (chloropropyl) potassium malonate (153 mmol) in 180 mL of ethanol was added to the reaction mixture. After the addition, the pH was adjusted to 4.5, the temperature was increased to room temperature and that temperature was maintained until the end of the reaction. Upon completion of the reaction, the pH was readjusted to 6.5, the ethanol was distilled in vacuo and extracted with 300 mL of methylene chloride. The organic phase was distilled under vacuum to obtain 43 g of an oil corresponding to the title product that was used directly in the next step.

EJEMPLO 2EXAMPLE 2

Síntesis de 3-(2-aminoetil)-[(S)-4-((l,3-oxazolidin-2-ona)ilmetil)-lH-indol-2- etoxicarbonilo [compuesto de fórmula (V)ISynthesis of 3- (2-aminoethyl) - [(S) -4 - ((l, 3-oxazolidin-2-one) ilmethyl) -lH-indole-2-ethoxycarbonyl [compound of formula (V) I

Al producto resultante del Ejemplo 1, etil-5-cloro-2-[[(S)-4-((l,3-oxazolidin-2- ona)ilmetil)fenil]hidrazin-2-ilideno]pentanoato, se añadieron 60 mL de una disolución al 70% de ácido fórmico en agua, y la mezcla se calentó a reflujo durante 45 minutos.To the product resulting from Example 1, ethyl-5-chloro-2 - [[(S) -4 - ((l, 3-oxazolidin-2- one) ilmethyl) phenyl] hydrazin-2-ylidene] pentanoate, 60 were added mL of a 70% solution of formic acid in water, and the mixture was heated at reflux for 45 minutes.

La disolución resultante se destiló hasta residuo y se cristalizó en etanol para obtener 10 g del compuesto del título como un sólido amarillo.The resulting solution was distilled to residue and crystallized from ethanol to obtain 10 g of the title compound as a yellow solid.

1H-RMN (400 MHz, DMSOd6): l,3(t, 3H, OCH2CHs); 2,7(t, 2H, CH2-CH2- NH2); 2,8(m, 2H, CH2-benc); 3,2(t, 2H, CH2-CH2-NH2); 4,0(m, 2H, 0-CH2-CH-); 4,2(t, IH, 0-CH2-CH-); 4,3(c, 2H, 0-CH2-CH3); 7,1 (d, IH, ar); 7,3(d, IH, ar); 7,6(s, IH, ar); 7,8(s, IH, CO-NH); l l,4(s, lH, NH-indol). 1 H-NMR (400 MHz, DMSOd 6 ): 1, 3 (t, 3H, OCH 2 CHs); 2.7 (t, 2H, CH 2 -CH 2 -NH 2 ); 2.8 (m, 2H, CH 2 -benc); 3.2 (t, 2H, CH 2 -CH 2 -NH 2 ); 4.0 (m, 2H, 0-CH 2 -CH-); 4.2 (t, IH, 0-CH 2 -CH-); 4.3 (c, 2H, 0-CH 2 -CH 3 ); 7.1 (d, IH, ar); 7.3 (d, IH, ar); 7.6 (s, IH, ar); 7.8 (s, IH, CO-NH); ll, 4 (s, lH, NH-indole).

13C-RMN (40 MHz, DMSO-d6): 15; 30; 41; 43; 53; 61; 68; 113; 121 ; 122; 124; 127; 128; 129; 136; 159; 162. 13 C-NMR (40 MHz, DMSO-d 6 ): 15; 30; 41; 43; 53; 61; 68; 113; 121; 122; 124; 127; 128; 129; 136; 159; 162.

EJEMPLO 3 Síntesis de 3-(2-aminoetil)-f(S)-4-((l,3-oxazolidin-2-ona)iImetil)-lH-indolEXAMPLE 3 Synthesis of 3- (2-aminoethyl) -f (S) -4 - ((l, 3-oxazolidin-2-one) imethyl) -lH-indole

[compuesto de fórmula (VII)T[compound of formula (VII) T

2 g del compuesto obtenido en el Ejemplo 2, 3-(2-aminoetil)-[(S)-4-((l,3- oxazolidin-2-ona)ilmetil)-lH-indol-2-etoxicarbonilo, se suspenden en 40 mL de una disolución al 10% de ácido sulfúrico en agua. La suspensión resultante se calentó a reflujo durante 8 horas. Completada la reacción, se paró con disolución de amoníaco al2 g of the compound obtained in Example 2, 3- (2-aminoethyl) - [(S) -4 - ((l, 3- oxazolidin-2-one) ilmethyl) -lH-indole-2-ethoxycarbonyl, are suspended in 40 mL of a 10% solution of sulfuric acid in water. The resulting suspension was heated at reflux for 8 hours. Upon completion of the reaction, it was stopped with ammonia solution at

10% y se destiló a vacío hasta residuo. El crudo de reacción se purificó por cromatografía de columna para obtener 1 g del compuesto del título como un sólido marrón.10% and distilled in vacuo to residue. The reaction crude was purified by column chromatography to obtain 1 g of the title compound as a brown solid.

EJEMPLO 4EXAMPLE 4

Síntesis de (4S)-4- \ [3- [2-(dimetilamino)etil)-lH-mdol-5-ill metili -2-oxazolidinonaSynthesis of (4S) -4- \ [3- [2- (dimethylamino) ethyl) -lH-mdol-5-ill methyli -2-oxazolidinone

[Zolmitriptánl 0,2 g del compuesto obtenido en el Ejemplo 3, 3-(2-aminoetil)-[(S)-4-((l,3- oxazolidin-2-ona)ilmetil)-lH-indol, se suspendieron en 2 mL de metanol y 0,28 mL de ácido acético a O0C. A la mezcla se añadieron 0,14 g de cianoborohidruro sódico, y, a continuación, una mezcla de 0,19 mL de formaldehído acuoso en 2 mL de metanol. Completada la adición, se mantuvo la temperatura a 25°C, hasta el final de la reacción. A la disolución resultante se añadieron 2 mL de agua y se destiló a vació hasta eliminar el metanol. A la mezcla resultante se añadieron 4 mL de cloruro de metileno y 2 mL de disolución de carbonato potásico al 20% y se agitó. La fase orgánica se destiló hasta residuo para obtener 0,2 g de una espuma amarilla, que se identificó como el producto del título. [Zolmitriptan 0.2 g of the compound obtained in Example 3, 3- (2-aminoethyl) - [(S) -4 - ((l, 3- oxazolidin-2-one) ilmethyl) -lH-indole, were suspended in 2 mL of methanol and 0.28 mL of acetic acid at 0 ° C. To the mixture was added 0.14 g of sodium cyanoborohydride, and then a mixture of 0.19 mL of aqueous formaldehyde in 2 mL of methanol Upon completion of the addition, the temperature was maintained at 25 ° C, until the end of the reaction. To the resulting solution, 2 mL of water was added and distilled under vacuum until methanol was removed. To the resulting mixture was added 4 mL of methylene chloride and 2 mL of 20% potassium carbonate solution and stirred. The organic phase was distilled to residue to obtain 0.2 g of a yellow foam, which was identified as the title product.

Claims

REIVINDICACIONES 1. Un procedimiento para la obtención de un derivado de triptamina de fórmula1. A procedure for obtaining a triptamine derivative of the formula (D(D
Figure imgf000018_0001
Figure imgf000018_0001
 (I) donde R se selecciona del grupo formado por:(I) where R is selected from the group consisting of: HH OOR <Λ N <Λ N X en donde X es O, NH, S o CH2, sus enantiómeros o mezclas de los mismos, o sus solvatos, hidratos o sales, que comprende a) descarboxilar un compuesto de fórmula (VI)X wherein X is O, NH, S or CH 2 , their enantiomers or mixtures thereof, or their solvates, hydrates or salts, which comprises a) decarboxylating a compound of formula (VI)
Figure imgf000018_0002
Figure imgf000018_0002
 (VI) donde R tiene el significado previamente indicado, para obtener un compuesto de fórmula (VII)(VI) where R has the previously indicated meaning, to obtain a compound of formula (VII)
Figure imgf000018_0003
Figure imgf000018_0003
 (VII) donde R tiene el significado previamente indicado, y b) someter dicho compuesto de fórmula (VII) a una reacción de aminometilación para obtener el compuesto de fórmula (I). (VII) where R has the previously indicated meaning, and b) subjecting said compound of formula (VII) to an aminomethylation reaction to obtain the compound of formula (I). 2. Procedimiento según la reivindicación 1, donde R es 2-oxo-l,3-oxazolidin-4- ilo ó 1,2,4-triazol-l-ilo.2. The method according to claim 1, wherein R is 2-oxo-l, 3-oxazolidin-4- yl or 1,2,4-triazol-l-yl. 3. Procedimiento según la reivindicación 1, en el que dicha reacción de aminometilación se lleva a cabo mediante aminación reductora en presencia de formaldehído y un agente reductor.3. The method according to claim 1, wherein said aminomethylation reaction is carried out by reductive amination in the presence of formaldehyde and a reducing agent. 4. Procedimiento según cualquiera de las reivindicaciones 1 a 3, en el que el compuesto de fórmula (I) obtenido es: (4S)-4-[[3-[2-(dimetilamino)etil)-lH-indol-5-il]metil]-2-oxazolidinona, o una sal farmacéuticamente aceptable del mismo, o4. Process according to any one of claims 1 to 3, wherein the compound of formula (I) obtained is: (4S) -4 - [[3- [2- (dimethylamino) ethyl) -lH-indole-5- il] methyl] -2-oxazolidinone, or a pharmaceutically acceptable salt thereof, or 3-[2-(dimetilamino)etil)]-5-(lH-l,2,4-triazol-l-ilmetil)indol, o una sal farmacéuticamente aceptable del mismo.3- [2- (dimethylamino) ethyl)] - 5- (lH-l, 2,4-triazol-l-ylmethyl) indole, or a pharmaceutically acceptable salt thereof. 5. Un compuesto de fórmula (IV)5. A compound of formula (IV)
Figure imgf000019_0001
Figure imgf000019_0001
 (IV) donde(IV) where R se selecciona del grupo formado por:R is selected from the group consisting of: H IH I Y i N y 0 Y i N y 0 en donde X es O, NH, S o CH2, R] es un grupo alquilo Ci-C8 lineal o ramificado, y HaI es halógeno. wherein X is O, NH, S or CH 2 , R] is a linear or branched Ci-C 8 alkyl group, and HaI is halogen. 6. Compuesto según la reivindicación 5, en el que R es 2-oxo-l,3-oxazolidin-4- ilo, Ri es etilo y HaI es cloro, o en el que R es 1,2,4-triazol-l-ilo, Ri es etilo y HaI es cloro.6. Compound according to claim 5, wherein R is 2-oxo-1, 3-oxazolidin-4-yl, Ri is ethyl and HaI is chlorine, or wherein R is 1,2,4-triazol-1 -ilo, Ri is ethyl and HaI is chlorine. 7. Un compuesto de fórmula (V)7. A compound of formula (V)
Figure imgf000020_0001
donde
Figure imgf000020_0001
where R se selecciona del grupo formado por:R is selected from the group consisting of: HH OOR X NJ en donde X es O, NH, S o CH2,X NJ where X is O, NH, S or CH 2 , Ri es un grupo alquilo Ci-C8 lineal o ramificado.Ri is a linear or branched Ci-C 8 alkyl group. 8. Compuesto según la reivindicación 7, en el que R es 2-oxo-l,3-oxazolidin-4- ilo y R] es etilo, o en el que R es 1,2,4-triazol-l-ilo y Ri es etilo.8. A compound according to claim 7, wherein R is 2-oxo-l, 3-oxazolidin-4- yl and R] is ethyl, or wherein R is 1,2,4-triazol-l-yl and Ri is ethyl. 9. Un compuesto de fórmula (VI)9. A compound of formula (VI)
Figure imgf000020_0002
Figure imgf000020_0002
 (VI) donde(VI) where R se selecciona del grupo formado por:R is selected from the group consisting of:
Figure imgf000020_0003
en donde X es O, NH, S o CH2.
Figure imgf000020_0003
where X is O, NH, S or CH 2 . 10. Compuesto según la reivindicación 9, en el que R es 2-oxo-l,3-oxazoridin~4- ilo, o en el que R es 1,2,4-triazol-l-ilo.10. A compound according to claim 9, wherein R is 2-oxo-1, 3-oxazoridin-4-yl, or wherein R is 1,2,4-triazol-1-yl. 11. Un procedimiento para la obtención de un derivado de triptamina de fórmula11. A procedure for obtaining a triptamine derivative of the formula 5 (I)5 (I)
Figure imgf000021_0001
Figure imgf000021_0001
 (I) donde R se selecciona del grupo formado por:(I) where R is selected from the group consisting of: V-X7 N-^ 0 en donde X es O, NH, S o CH2, sus enantiómeros o mezclas de los mismos, o sus solvatos, hidratos o sales, que comprende a) hacer reaccionar la sal de arildiazonio formada a partir de un compuesto de fórmula (II)VX 7 N- ^ 0 wherein X is O, NH, S or CH 2 , its enantiomers or mixtures thereof, or its solvates, hydrates or salts, comprising a) reacting the aryldiazonium salt formed from a compound of formula (II)
Figure imgf000021_0002
Figure imgf000021_0002
 (H) donde R tiene el significado previamente mencionado; con la monosal alquil 3-(halopropil)malonato potásico de fórmula (III)(H) where R has the previously mentioned meaning; with the monosal alkyl 3- (halopropyl) potassium malonate of formula (III)
Figure imgf000021_0003
0 (III) donde
Figure imgf000021_0003
0 (III) where Ri es un grupo alquilo Ci-Cg lineal o ramificado, y HaI es halógeno, para formar el compuesto de fórmula (IV)Ri is a linear or branched Ci-Cg alkyl group, and HaI is halogen, to form the compound of formula (IV)
Figure imgf000022_0001
Figure imgf000022_0001
 (IV) donde R, Ri y HaI tienen los significados previamente indicados; b) someter el compuesto de fórmula (IV) a una reacción de ciclación de Fisher para formar un compuesto de fórmula (V)(IV) where R, Ri and HaI have the previously indicated meanings; b) subjecting the compound of formula (IV) to a Fisher cyclisation reaction to form a compound of formula (V)
Figure imgf000022_0002
donde R y Ri tienen los significados previamente indicados; c) hidrolizar el grupo éster del compuesto de fórmula (V) para obtener el compuesto de fórmula (VI)
Figure imgf000022_0002
where R and Ri have the meanings previously indicated; c) hydrolyzing the ester group of the compound of formula (V) to obtain the compound of formula (VI)
Figure imgf000022_0003
Figure imgf000022_0003
 (VI) donde R tiene el significado previamente indicado; d) descarboxilar dicho compuesto de fórmula (VI) para obtener un compuesto de fórmula (VII)(VI) where R has the previously indicated meaning; d) decarboxylating said compound of formula (VI) to obtain a compound of formula (VII)
Figure imgf000022_0004
Figure imgf000022_0004
 (VII) donde R tiene el significado previamente indicado, y e) someter dicho compuesto de fórmula (VII) a una reacción de aminometilación para obtener el compuesto de fórmula (I). (VII) where R has the previously indicated meaning, and e) subjecting said compound of formula (VII) to an aminomethylation reaction to obtain the compound of formula (I). 12. Procedimiento según la reivindicación 11, en el que el compuesto de fórmula (I) obtenido es:12. The method according to claim 11, wherein the compound of formula (I) obtained is: (4S)-4-[[3-[2-(dimetilamino)etil)-l/í-indol-5-il]metil]-2-oxazolidinona, o una sal farmacéuticamente aceptable del mismo, o(4S) -4 - [[3- [2- (dimethylamino) ethyl) -l / í-indole-5-yl] methyl] -2-oxazolidinone, or a pharmaceutically acceptable salt thereof, or 3-[2-(dimetilamino)etil)]-5-(lH-l,2,4-tria2ol-l-ilmetil)indol, o una sal farmacéuticamente aceptable del mismo. 3- [2- (dimethylamino) ethyl)] - 5- (lH-l, 2,4-tria2ol-l-ylmethyl) indole, or a pharmaceutically acceptable salt thereof.
PCT/ES2006/000465 2005-08-08 2006-08-07 Method of obtaining tryptamine derivatives Ceased WO2007017546A2 (en)

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