WO2012076736A1 - Deuterated phenacyl and derivatives, method for the preparation thereof and uses thereof - Google Patents

Deuterated phenacyl and derivatives, method for the preparation thereof and uses thereof Download PDF

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WO2012076736A1
WO2012076736A1 PCT/ES2011/000361 ES2011000361W WO2012076736A1 WO 2012076736 A1 WO2012076736 A1 WO 2012076736A1 ES 2011000361 W ES2011000361 W ES 2011000361W WO 2012076736 A1 WO2012076736 A1 WO 2012076736A1
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group
deuterated
compound
acid
formula
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PCT/ES2011/000361
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Spanish (es)
French (fr)
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Victor Morales Alcazar
David Arraez Roman
Antonio Segura Carretero
José JUSTICIA LADRON DE GUEVARA
Antonio Rosales Martinez
Juan Enrique Oltra Ferrero
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Universidad De Granada
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/56—One oxygen atom and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention relates to the design, synthesis and applications of deuterated derivatives of certain tyrostatic compounds.
  • tyrostatic compounds are orally active drugs that can be used in the fraudulent fattening of cattle prior to slaughter.
  • the main consequences of the abuse of these compounds are not only obtaining lower quality meat, but the potential risk they constitute for human health. For these reasons, the use of these compounds has been banned within the framework of the European Union since 1981 (directive 81/602 / EC)
  • tyrostatic compounds 6-phenyl-2-thioxo-2, 3-dihydropyridin-4 (1H) -one, also known as Fenucil.
  • Fenucil 6-phenyl-2-thioxo-2, 3-dihydropyridin-4 (1H) -one, also known as Fenucil.
  • no deuterated derivatives thereof are known in the state of the art.
  • the object of the present invention is the chemical preparation of a deuterated isotopomer of the compound 6-phenyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one, also known as Fenucil, as well as other derivatives thereof, specifically, the deuterated compound of formula (I)
  • Ri / R 2 and R 3 independently represent a hydrogen atom or a C 1 -C alkyl group substituted with:
  • R 4 is a hydrogen atom or a C 1 -C 3 alkyl group optionally substituted with phenyl;
  • R 5 and R 6 being independently a hydrogen atom, or a C 1 -C 3 alkyl group, tosyl or mesyl;
  • R 7 is a hydrogen atom or a C-C 3 alkyl group
  • R 8 is a C 1 -C 3 alkyl or phenyl group
  • D represents deuterium
  • Another object of the invention is the deuterated compound itself (I).
  • Another object of the invention is to provide a pharmaceutical composition comprising said deuterated compound.
  • Another object of the invention is to provide the use of said deuterated compound to manufacture drugs intended for the treatment of hyperthyroidism or to use as a standard in the detection of the corresponding tyrostatic compound.
  • the present invention provides the deuterated compound of general formula (I)
  • Ri, R 2 and R 3 independently represent hydrogen, either a methyl or ethyl group that is substituted with a hydroxy (-0H), methoxy (-OMe), ethoxy group (-OEt), benzyloxy (-OBn), amine (-NH 2 ), methylamine (-NHMe), ethylamine (-NHEt), tosylamine (-NHTs), mesylamine (-NHMs), thiol (-SH), thiomethoxy ( -SMe), thioethoxy (-SEt), acetoxy (- OCOCH 3 ) or benzoyloxy (-OBz); or with a fluorine, chlorine, bromine or iodine atom.
  • Ri, R 2 and R 3 independently represent hydrogen or methyl. In an even more preferred embodiment, R lt R 2 and R 3 represent hydrogen.
  • the preferred deuterated compound of formula (I) of the invention is 6-pentadeuterophenyl-2-thioxo-2, 3-dihydropyridin-4 (1H) -one.
  • R 3 has the meanings given previously, with deuterated benzene (C 6 D 6 ) in the presence of a Lewis acid at elevated temperature, according to a Friedel-Crafts acylation reaction.
  • step (b) reacting the deuterated derivative acyl obtained in step (a) with the compound (2) in the presence of a strong base at elevated temperature;
  • step (c) treating the reaction product of step (b) with an acid until acidic pH.
  • the acylation of the corresponding compound is carried out using a suitable Lewis acid, preferably at reflux.
  • Lewis acid in particular, aluminum bromide (AlBr 3 ) or, preferably, aluminum chloride (A1C1 3 ) can be used
  • the solvent used in this step (a) will be any suitable solvent of the state of the art, such as tetrahydrofuran (THF), diethyl ether (Et 2 0) or without solvent, the deuterated benzene itself (C 6 H 6 ) acting as such, for example, although it is preferred without solvent, the deuterated benzene itself (C 6 H 6 ) acting as such.
  • this reaction is carried out between 20 and 150 ° C, with an optimum yield at 90 ° C and for a time of 5 minutes to 1 hour, preferably 20 minutes.
  • the reaction product is treated with a strong base at elevated temperature.
  • the strong base employed in step (b) is selected from a metal hydride such as sodium hydride or potassium hydride; a metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; a metal alkoxide such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide or potassium ethoxide; a metal amide such as lithium amide, sodium amide, potassium amide or lithium diisopropyl amide (LDA); a nitrogen organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); a metal hexamethyldisilazide such as lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide; or an
  • the strong base employed in step (b) is sodium ethoxide.
  • the reaction with the strong base of step (b) is carried out at a temperature between 40 ° C and l30 ° C, preferably at a temperature between 60 to 120 ° C and, more preferably, at a temperature of 90 ° C
  • the time necessary for the reaction to be effective is between 5 and 48 hours, preferably for a time between 10 and 24 hours and, more preferably, for a time of 20 hours.
  • step (c) the product accildeuterated and treated with the strong base at high temperature is reacted, step (c), with an acid until acidic pH.
  • the acid reagent can be used, in particular sulfuric acid (H 2 S0 4 ), nitric acid (HN0 3 ), phosphoric acid (H 3 PO 4 ), or, preferably, hydrochloric acid (HC1).
  • the reaction with the strong acid of step (c) is carried out at a temperature between 5 ° C and 30 ° C, preferably at a temperature between 10 to 25 ° C and, more preferably, at a temperature of 18 ° C
  • This reaction with the strong acid of step (c) is carried out for a time of between 1 and 15 minutes, more preferably for a time of 5 minutes.
  • the solvent used in this step (c) will be any suitable solvent of the state of the art, such as absolute ethanol (EtOH), tetrahydrofuran (THF) or diethyl ether (Et 2 0), for example, although absolute ethanol is preferred.
  • EtOH absolute ethanol
  • THF tetrahydrofuran
  • Et 2 0 diethyl ether
  • a pharmaceutical composition which comprises the compound of the invention defined previously and, at least, a pharmaceutically acceptable excipient.
  • a pharmaceutical composition which comprises the compound of the invention defined previously and, at least, a pharmaceutically acceptable excipient.
  • the use of previously defined compounds for the manufacture of medicaments for the treatment of hyperthyroidism is provided.
  • the deuterated compound of the invention can be used as a standard in the detection of the corresponding tyrostatic compound.
  • Ri, R 2 and R 3 have the meanings given previously, using high resolution chromatographic techniques combined with mass spectrometry.
  • HPLC high performance liquid chromatography
  • GC gas chromatography
  • the compound obtained was treated with sodium ethoxide and thiourea (SC (NH 2 ) 2 ) in absolute ethanol (EtOH) and the mixture was heated at reflux for 18 h. 10% HC1 solution was added until acidic pH, ethanol (EtOH) was removed under reduced pressure. The precipitate appeared was collected and washed with hexane giving a yield of 80%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention defines deuterated compounds of formula (I) in which: R1, R2 and R3 independently represent a hydrogen atom or C1-C4 alkyl group, optionally substituted with an -OR4 group; R4 being a hydrogen atom or a C1-C3 alkyl group optionally substituted with phenyl; a -NR5Re group, R5 and Re independently being a hydrogen atom or a C1-C3 alkyl, tosyl or mesyl group; a -SR7 group, R7 being a hydrogen atom or C1-C3 alkyl group; a -OCOR8 group, R8 being a C1-C3 alkyl or phenyl group; or a halogen atom; and D represents deuterium. The invention also defines a method for preparing said deuterated compounds, a pharmaceutical composition that comprises said compounds and the use thereof in the pharmaceutical and analytical fields.

Description

FENUCIL DEÜTERADQ Y DERIVADOS, PROCEDIMIENTO PARA Sü PREPARACIÓN Y ÜSOS DE LOS MISMOS. FENUCIL DEÜTERADQ AND DERIVATIVES, PROCEDURE FOR THEIR PREPARATION AND THE SAME OF THEM.
INTRODUCCIÓN INTRODUCTION
La invención se refiere al diseño, síntesis y aplicaciones de derivados deuterados de determinados compuestos tireostáticos . The invention relates to the design, synthesis and applications of deuterated derivatives of certain tyrostatic compounds.
ESTADO DE LA TÉCNICA STATE OF THE TECHNIQUE
Como es bien conocido en el estado de la técnica, los compuestos tireostáticos son fármacos activos por vía oral que se pueden emplear en el engorde fraudulento del ganado previamente a su sacrificio. Las principales consecuencias del abuso de estos compuestos no son sólo la obtención de carne de menor calidad, sino el riesgo potencial que constituyen para la salud humana. Por estas razones, el uso de estos compuestos se encuentra prohibido en el marco de la Unión Europea desde 1981 (directiva 81/602/EC) As is well known in the state of the art, tyrostatic compounds are orally active drugs that can be used in the fraudulent fattening of cattle prior to slaughter. The main consequences of the abuse of these compounds are not only obtaining lower quality meat, but the potential risk they constitute for human health. For these reasons, the use of these compounds has been banned within the framework of the European Union since 1981 (directive 81/602 / EC)
La detección de estos compuestos en muestras de diversa procedencia (orina, leche, carne, sangre, muestras de tiroides) resulta problemática debido a la existencia de formas tautoméricas de los mismos, además de por presentar una elevada polaridad, lo que dificulta enormemente su detección empleando cromatografía líquida de alta resolución de fase reversa (RP-HPLC) . The detection of these compounds in samples of diverse origin (urine, milk, meat, blood, thyroid samples) is problematic due to the existence of tautomeric forms thereof, in addition to presenting a high polarity, which greatly hinders their detection using reverse phase high resolution liquid chromatography (RP-HPLC).
Adicionalmente, el estudio mediante espectrometría de masas de estos compuestos de bajo peso molecular no es satisfactorio en términos de sensibilidad (relación señal/ruido de fondo), ya que frecuentemente las señales debidas a estas moléculas aparecen solapadas con el ruido de fondo . Sin embargo, las técnicas de cromatografía líquida de alta resolución (HPLC) y de cromatografía de gases (GC) acopladas a espectrometría de masas son las más utilizadas en la detección de este tipo de compuestos . Una reciente directiva de la Unión Europea (96/23/CE) , indica que el uso de derivados deuterados de los compuestos tireostáticos a analizar constituye un método analítico de alta precisión para la detección de estos compuestos [E.C. Council directive 96/23/CE, Off. J. Eur. Cowmun. 2002 L221/8] . Additionally, the study by mass spectrometry of these low molecular weight compounds is not satisfactory in terms of sensitivity (signal to background noise ratio), since the signals due to these molecules frequently overlap with background noise. However, high performance liquid chromatography (HPLC) and gas chromatography (GC) techniques coupled to mass spectrometry are the most commonly used in the detection of such compounds. A recent European Union directive (96/23 / EC), indicates that the use of deuterated derivatives of the tyrostatic compounds to be analyzed constitutes a high precision analytical method for the detection of these compounds [EC Council directive 96/23 / CE , Off. J. Eur. Cowmun. 2002 L221 / 8].
Continúa existiendo, por tanto, la necesidad de proporcionar nuevos derivados deuterados de los compuestos tireostáticos para la detección fiable y precisa de los mismos mediante técnicas cromatográficas de alta resolución combinadas con espectrometría de masas . There remains, therefore, the need to provide new deuterated derivatives of the tyrostatic compounds for reliable and accurate detection thereof by means of high resolution chromatographic techniques combined with mass spectrometry.
Uno de estos compuestos tireostáticos es el 6-fenil-2- tioxo-2 , 3-dihidropiridin-4 (1H) -ona, conocido también como Fenucil. Sin embargo, no se conoce en el estado de la técnica ningún derivado deuterados del mismo. One of these tyrostatic compounds is 6-phenyl-2-thioxo-2, 3-dihydropyridin-4 (1H) -one, also known as Fenucil. However, no deuterated derivatives thereof are known in the state of the art.
OBJETO DE LA INVENCIÓN OBJECT OF THE INVENTION
El objeto de la presente invención es la preparación química de un isotopómero deuterado del compuesto 6-fenil-2-tioxo- 2 , 3-dihidropiridin-4 (1H) -ona, conocido también como Fenucil, así como de otros derivados del mismo, concretamente, el compuesto deuterado de fórmula (I) The object of the present invention is the chemical preparation of a deuterated isotopomer of the compound 6-phenyl-2-thioxo-2,3-dihydropyridin-4 (1H) -one, also known as Fenucil, as well as other derivatives thereof, specifically, the deuterated compound of formula (I)
Figure imgf000005_0001
Figure imgf000005_0001
(I) la que:  (I) the one that:
Ri / R2 y R3 representan de forma independiente un átomo de hidrógeno o un grupo alquilo C1-C sustituido con: Ri / R 2 and R 3 independently represent a hydrogen atom or a C 1 -C alkyl group substituted with:
un grupo -0R4 / siendo R4 un átomo de hidrógeno o un grupo alquilo C1-C3 opcionalmente sustituido con fenilo; a group -0R 4 / where R 4 is a hydrogen atom or a C 1 -C 3 alkyl group optionally substituted with phenyl;
un grupo -NR5R6, siendo R5 y R6 de forma independiente un átomo de hidrógeno, o un grupo alquilo C1-C3, tosilo o mesilo; a -NR 5 R 6 group , R 5 and R 6 being independently a hydrogen atom, or a C 1 -C 3 alkyl group, tosyl or mesyl;
un grupo -SR7, siendo R7 un átomo de hidrógeno o un grupo alquilo Ci- C3 ; a group -SR 7 , where R 7 is a hydrogen atom or a C-C 3 alkyl group;
un grupo -OCOR8/ siendo R8 un grupo alquilo C1-C3 o fenilo; o a group -OCOR 8 / where R 8 is a C 1 -C 3 alkyl or phenyl group; or
un átomo de halógeno; y  a halogen atom; Y
D representa deuterio.  D represents deuterium.
Otro objeto de la invención es el propio compuesto deuterado (I) . Another object of the invention is the deuterated compound itself (I).
Asimismo, otro objeto de la invención es proporcionar una composición farmacéutica que comprende dicho compuesto deuterado . Also, another object of the invention is to provide a pharmaceutical composition comprising said deuterated compound.
Finalmente, otro objeto de la invención es proporcionar el uso de dicho compuesto deuterado para fabricar medicamentos destinados al tratamiento del hipertiroidismo o para usar como patrón en la detección del compuesto tireostático correspondiente . Finally, another object of the invention is to provide the use of said deuterated compound to manufacture drugs intended for the treatment of hyperthyroidism or to use as a standard in the detection of the corresponding tyrostatic compound.
DESCRIPCIÓN DETALLADA DE LA INVENCIÓN DETAILED DESCRIPTION OF THE INVENTION
La presente invención proporciona el compuesto deuterado de fórmula general (I) The present invention provides the deuterated compound of general formula (I)
En una realización particular del compuesto deuterado de la invención, Ri, R2 y R3 representan de forma independiente hidrógeno, o bien un grupo metilo o etilo que está sustituido con un grupo hidroxi (-0H), metoxi (-OMe) , etoxi(-OEt), benciloxi (-OBn) , amina (-NH2) , metilamina ( -NHMe ) , etilamina (-NHEt) , tosilamina (-NHTs) , mesilamina (-NHMs) , tiol (-SH) , tiometoxi (-SMe) , tioetoxi (-SEt) , acetoxi (- OCOCH3) o benzoiloxi (-OBz); o con un átomo de flúor, cloro, bromo o yodo. In a particular embodiment of the deuterated compound of the invention, Ri, R 2 and R 3 independently represent hydrogen, either a methyl or ethyl group that is substituted with a hydroxy (-0H), methoxy (-OMe), ethoxy group (-OEt), benzyloxy (-OBn), amine (-NH 2 ), methylamine (-NHMe), ethylamine (-NHEt), tosylamine (-NHTs), mesylamine (-NHMs), thiol (-SH), thiomethoxy ( -SMe), thioethoxy (-SEt), acetoxy (- OCOCH 3 ) or benzoyloxy (-OBz); or with a fluorine, chlorine, bromine or iodine atom.
En una realización preferida, Ri, R2 y R3 representan de forma independiente hidrógeno o metilo. En una realización aún más preferida, Rlt R2 y R3 representan hidrógeno. In a preferred embodiment, Ri, R 2 and R 3 independently represent hydrogen or methyl. In an even more preferred embodiment, R lt R 2 and R 3 represent hydrogen.
Así, el compuesto deuterado de fórmula (I) preferido de la invención es 6-pentadeuterofenil-2-tioxo-2 , 3-dihidropiridin- 4(lH)-ona. Thus, the preferred deuterated compound of formula (I) of the invention is 6-pentadeuterophenyl-2-thioxo-2, 3-dihydropyridin-4 (1H) -one.
En otro aspecto de la invención se proporciona un procedimiento para preparar el compuesto deuterado de la invención previamente descrito, que comprende las etapas siguientes: In another aspect of the invention there is provided a process for preparing the deuterated compound of the invention previously described, which comprises the following steps:
(a) hacer reaccionar un compuesto de fórmula (1) , (a) reacting a compound of formula (1),
Figure imgf000007_0001
Figure imgf000007_0001
en la que R3 tiene los significados dados previamente, con benceno deuterado (C6D6) en presencia de un ácido de Lewis a elevada temperatura, según una reacción de acilación de Friedel-Crafts . wherein R 3 has the meanings given previously, with deuterated benzene (C 6 D 6 ) in the presence of a Lewis acid at elevated temperature, according to a Friedel-Crafts acylation reaction.
(b) hacer reaccionar el acil derivado deuterado obtenido en la etapa (a) con el compuesto (2) en presencia de una base fuerte a temperatura elevada; (b) reacting the deuterated derivative acyl obtained in step (a) with the compound (2) in the presence of a strong base at elevated temperature;
Figure imgf000007_0002
en la que Ri y R2 tienen los significados dados previamente .
Figure imgf000007_0002
wherein Ri and R 2 have the previously given meanings.
(c) tratar el producto de reacción de la etapa (b) con un ácido hasta pH ácido. (c) treating the reaction product of step (b) with an acid until acidic pH.
En la primera etapa del procedimiento, la acilación del compuesto correspondiente se efectúa empleando un ácido de Lewis adecuado, preferentemente a reflujo. Como ácido de Lewis se puede emplear, en particular, bromuro de aluminio (AlBr3) o, preferentemente , cloruro de aluminio (A1C13) El disolvente empleado en esta etapa (a) será cualquier disolvente adecuado del estado de la técnica, tal como tetrahidrofurano (THF) , dietiléter (Et20) o sin disolvente, actuando el propio benceno deuterado (C6H6) como tal, por ejemplo, si bien se prefiere sin disolvente, actuando el propio benceno deuterado (C6H6) como tal. Asimismo, esta reacción se efectúa entre 20 y 150 °C, con un rendimiento óptimo a 90 °C y durante un tiempo de 5 minutos a 1 hora, preferiblemente de 20 minutos. In the first stage of the process, the acylation of the corresponding compound is carried out using a suitable Lewis acid, preferably at reflux. As Lewis acid, in particular, aluminum bromide (AlBr 3 ) or, preferably, aluminum chloride (A1C1 3 ) can be used The solvent used in this step (a) will be any suitable solvent of the state of the art, such as tetrahydrofuran (THF), diethyl ether (Et 2 0) or without solvent, the deuterated benzene itself (C 6 H 6 ) acting as such, for example, although it is preferred without solvent, the deuterated benzene itself (C 6 H 6 ) acting as such. Also, this reaction is carried out between 20 and 150 ° C, with an optimum yield at 90 ° C and for a time of 5 minutes to 1 hour, preferably 20 minutes.
Tras la reacción de la etapa (a) , el producto de reacción se trata con una base fuerte a elevada temperatura. Así, en otra realización particular del procedimiento de la invención, la base fuerte empleada en la etapa (b) se selecciona entre un hidruro metálico tal como el hidruro sódico o el hidruro potásico; un hidróxido metálico tal como el hidróxido de litio, el hidróxido de sodio o el hidróxido de potasio; un alcóxido metálico tal como el metóxido de litio, el metóxido de sodio, el metóxido de potasio, el etóxido de litio, el etóxido de sodio o el etóxido de potasio; un amiduro metálico tal como el amiduro de litio, el amiduro de sodio, el amiduro de potasio o el diisopropil amiduro de litio (LDA) ; una base orgánica nitrogenada tales como la 1 , 8-diazabiciclo [5.4.0] undec-7-eno (DBU) ; una hexametildisilazida metálica tal como la hexametildisilazida de litio, la hexametildisilazida de sodio o la hexametildisilazida de potasio; o un alquilmetal tal como el tert-butil litio o el butil litio. After the reaction of step (a), the reaction product is treated with a strong base at elevated temperature. Thus, in another particular embodiment of the process of the invention, the strong base employed in step (b) is selected from a metal hydride such as sodium hydride or potassium hydride; a metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; a metal alkoxide such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide or potassium ethoxide; a metal amide such as lithium amide, sodium amide, potassium amide or lithium diisopropyl amide (LDA); a nitrogen organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU); a metal hexamethyldisilazide such as lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide; or an alkyl metal such as tert-butyl lithium or butyl lithium.
Así, en una realización preferida del procedimiento de la invención, la base fuerte empleada en la etapa (b) es etóxido de sodio. La reacción con la base fuerte de la etapa (b) se efectúa a una temperatura de entre 40 °C y l30 °C, preferiblemente a una temperatura de entre 60 a 120 °C y, más preferiblemente, a una temperatura de 90 °C.E1 tiempo necesario para que reacción sea efectiva está comprendido entre 5 y 48 horas, preferiblemente durante un tiempo de entre 10 y 24 horas y, más preferiblemente, durante un tiempo de 20 horas. Thus, in a preferred embodiment of the process of the invention, the strong base employed in step (b) is sodium ethoxide. The reaction with the strong base of step (b) is carried out at a temperature between 40 ° C and l30 ° C, preferably at a temperature between 60 to 120 ° C and, more preferably, at a temperature of 90 ° C The time necessary for the reaction to be effective is between 5 and 48 hours, preferably for a time between 10 and 24 hours and, more preferably, for a time of 20 hours.
Finalmente, el producto acildeuterado y tratado con la base fuerte a alta temperatura se hace reaccionar, etapa (c) , con un ácido hasta pH ácido. Finally, the product accildeuterated and treated with the strong base at high temperature is reacted, step (c), with an acid until acidic pH.
Como reactivo ácido se puede emplear, en particularácido sulfúrico (H2S04) , ácido nítrico (HN03) , ácido fosfórico (H3PO4) , o, preferentemente, ácido clorhídrico (HC1) . The acid reagent can be used, in particular sulfuric acid (H 2 S0 4 ), nitric acid (HN0 3 ), phosphoric acid (H 3 PO 4 ), or, preferably, hydrochloric acid (HC1).
La reacción con el ácido fuerte de la etapa (c) se efectúa a una temperatura de entre 5 °C y 30 °C, preferiblemente a una temperatura de entre 10 a 25 °C y, más preferiblemente, a una temperatura de 18 °C.Esta reacción con el ácido fuerte de la etapa (c) se efectúa durante un tiempo de entre 1 y 15 minutos, más preferiblemente durante un tiempo de 5 minutos. The reaction with the strong acid of step (c) is carried out at a temperature between 5 ° C and 30 ° C, preferably at a temperature between 10 to 25 ° C and, more preferably, at a temperature of 18 ° C This reaction with the strong acid of step (c) is carried out for a time of between 1 and 15 minutes, more preferably for a time of 5 minutes.
El disolvente empleado en esta etapa (c) será cualquier disolvente adecuado del estado de la técnica, tal como etanol absoluto (EtOH) , tetrahidrofurano (THF) o dietiléter (Et20) , por ejemplo, si bien se prefiere el etanol absoluto. The solvent used in this step (c) will be any suitable solvent of the state of the art, such as absolute ethanol (EtOH), tetrahydrofuran (THF) or diethyl ether (Et 2 0), for example, although absolute ethanol is preferred.
En otro aspecto de la invención se proporciona una composición farmacéutica, que comprende el compuesto de la invención definido previamente y, al menos, un excipiente farmacéuticamente aceptable. En otro aspecto de la invención se proporciona el uso de los compuestos definidos previamente para la fabricación de medicamentos para el tratamiento del hipertiroidismo . In another aspect of the invention there is provided a pharmaceutical composition, which comprises the compound of the invention defined previously and, at least, a pharmaceutically acceptable excipient. In another aspect of the invention the use of previously defined compounds for the manufacture of medicaments for the treatment of hyperthyroidism is provided.
Por otro lado, el compuesto deuterado de la invención se puede usar como patrón en la detección del compuesto tireostático correspondiente. On the other hand, the deuterated compound of the invention can be used as a standard in the detection of the corresponding tyrostatic compound.
Así, en otro aspecto de la invención se proporciona el uso del compuestos deuterado de la invención (I) , y sus derivados definidos previamente, como patrones para la detección de compuestos tireost II) . Thus, in another aspect of the invention there is provided the use of the deuterated compounds of the invention (I), and their previously defined derivatives, as standards for the detection of tireost compounds II).
Figure imgf000010_0001
Figure imgf000010_0001
(ID (ID
en la que Ri, R2 y R3 tienen los significados dados previamente, mediante técnicas cromatográficas de alta resolución combinadas con espectrometría de masas. in which Ri, R 2 and R 3 have the meanings given previously, using high resolution chromatographic techniques combined with mass spectrometry.
Entre estas técnicas cromatográficas que pueden emplearse están la cromatografía liquida de alta resolución (HPLC) y la cromatografía de gases (GC) . MODO DE REALIZACION Among these chromatographic techniques that can be used are high performance liquid chromatography (HPLC) and gas chromatography (GC). MODE OF REALIZATION
Preparación de 6-pentadeuterofenil-2 -tioxo-2 , 3■ dihidropiridin- (1H) -ona (Fenucil deuterado). Preparation of 6-pentadeuterophenyl-2-thioxo-2, 3 ■ dihydropyridin- (1 H) -one (deuterated fenucil).
Figure imgf000011_0001
Figure imgf000011_0001
Una disolución de 897 mg de cloruro de metil malonilo comercial en benceno deuterado (C6D6) (0,37 mi) se calentó a reflujo durante 20 minutos. Transcurrido este tiempo se dejó enfriar y el crudo de reacción se virtió sobre hielo adicionándole disolución de hidróxido sódico (NaOH) al 10% hasta pH básico. Se extrajo con dietiléter (Et20) y la fase orgánica se secó con Na2S04 anhidro, se filtró y evaporó el disolvente para dar un compuesto deuterado con un rendimiento del 90%. A solution of 897 mg of commercial methyl malonyl chloride in deuterated benzene (C 6 D 6 ) (0.37 ml) was heated at reflux for 20 minutes. After this time, it was allowed to cool and the reaction crude was poured onto ice by adding 10% sodium hydroxide solution (NaOH) to basic pH. It was extracted with diethyl ether (Et 2 0) and the organic phase was dried with anhydrous Na 2 S0 4 , filtered and the solvent evaporated to give a deuterated compound with a yield of 90%.
Posteriormente, el compuesto obtenido se trató con etóxido de sodio y tiourea (SC(NH2)2) en etanol (EtOH) absoluto y la mezcla se calentó a reflujo durante 18 h. Se añadió disolución de HC1 al 10% hasta pH ácido, se eliminó el etanol (EtOH) a presión reducida. El precipitado aparecido se recogió y se lavó con hexano dando un rendimiento del 80%. Subsequently, the compound obtained was treated with sodium ethoxide and thiourea (SC (NH 2 ) 2 ) in absolute ethanol (EtOH) and the mixture was heated at reflux for 18 h. 10% HC1 solution was added until acidic pH, ethanol (EtOH) was removed under reduced pressure. The precipitate appeared was collected and washed with hexane giving a yield of 80%.

Claims

REIVINDICACIONES
1. Compuesto deuterado de fórmula 1. Deuterated compound of formula
Figure imgf000012_0001
Figure imgf000012_0001
(I) en la que :  (I) in which:
Ri R2 y R3 representan de forma independiente un átomo de hidrógeno o un grupo alquilo C1-C4, opcionalmente sustituido con Ri R 2 and R 3 independently represent a hydrogen atom or a C 1 -C 4 alkyl group, optionally substituted with
un grupo -OR4, siendo R4 un átomo de hidrógeno o un grupo alquilo C1-C3 opcionalmente sustituido con fenilo; a -OR 4 group, R 4 being a hydrogen atom or a C 1 -C 3 alkyl group optionally substituted with phenyl;
un grupo - R5R6, siendo R5 y R6 de forma independiente un átomo de hidrógeno, o un grupo alquilo Ci-C3f tosilo o mesilo; a group - R 5 R 6 , R 5 and R 6 being independently a hydrogen atom, or a Ci-C 3f alkyl or tosyl group;
un grupo -SR7/ siendo R7 un átomo de hidrógeno o un grupo alquilo Ci-C3; a group -SR 7 / where R 7 is a hydrogen atom or a Ci-C 3 alkyl group;
un grupo -OCOR8, siendo R8 un grupo alquilo C1-C3 o fenilo; o a -OCOR 8 group, R 8 being a C 1 -C 3 alkyl or phenyl group; or
un átomo de halógeno; y  a halogen atom; Y
D representa deuterio.  D represents deuterium.
2. Compuestos según la reivindicación 1, caracterizados porque Ri# R2 y R3 representan de forma independiente hidrógeno, o un grupo metilo o etilo opcionalmente sustituido con un grupo hidroxi, metoxi, etoxi, benciloxi, amina, metilamina, etilamina, tosilamina, mesilamina, tiol, tiometoxi, tioetoxi, acetoxi o benzoiloxi; o con un átomo de flúor, cloro, bromo o yodo. 2. Compounds according to claim 1, characterized in that R i # R 2 and R 3 independently represent hydrogen, or a methyl or ethyl group optionally substituted with a hydroxy, methoxy, ethoxy, benzyloxy, amine, methylamine, ethylamine, tosylamine, mesylamine, thiol, thiomethoxy, thioethoxy, acetoxy or benzoyloxy group; or with a fluorine, chlorine, bromine or iodine atom.
3. Compuestos según la reivindicación 2 , caracterizados porque Rx, R2 y R3 representan de forma independiente hidrógeno o metilo. 3. Compounds according to claim 2, wherein R x, R 2 and R3 independently represent hydrogen or methyl.
4. Procedimiento para la preparación del compuesto de fórmula (I) que comprende las siguientes etapas : hacer reaccionar un compuesto de fórmula 4. Process for the preparation of the compound of formula (I) comprising the following steps: reacting a compound of formula
Figure imgf000013_0001
en la que R3 tiene los significados dados previamente, con benceno deuterado (C6D&) en presencia de un ácido de Lewis a elevada temperatura, según una reacción de acilación de Friedel-Crafts .
Figure imgf000013_0001
in which R 3 has the meanings given previously, with deuterated benzene (C 6 D & ) in the presence of a Lewis acid at elevated temperature, according to a Friedel-Crafts acylation reaction.
(b) hacer reaccionar el acil derivado deuterado obtenido en la etapa (a) con el compuesto (2) en presencia de una base fuerte a temperatura elevada; (b) reacting the deuterated derivative acyl obtained in step (a) with the compound (2) in the presence of a strong base at elevated temperature;
Figure imgf000013_0002
Figure imgf000013_0002
(2) en la que Ri y R2 tienen los significados dados previamente . (2) wherein Ri and R 2 have the previously given meanings.
(c) tratar el producto de reacción de la etapa (b) con un ácido hasta pH ácido. (c) treating the reaction product of step (b) with an acid until acidic pH.
5. Procedimiento según la reivindicación 4, caracterizado porque el reactivo deuterado empleado en la etapa (a) es benceno deuterado (C6D6) . 5. Method according to claim 4, characterized in that the deuterated reagent used in step (a) is deuterated benzene (C 6 D 6 ).
6. Procedimiento según reivindicaciones 4 ó 5, caracterizado porque el ácido se Lewis empleado en la etapa (a) se selecciona entre cloruro de aluminio (A1C13) o bromuro de aluminio (AlBr3) . Method according to claims 4 or 5, characterized in that the acid Lewis used in step (a) is selected from aluminum chloride (A1C1 3 ) or aluminum bromide (AlBr 3 ).
7. Procedimiento según la reivindicación 6, caracterizado porque el ácido de Lewis empleado en la etapa (a) es cloruro de aluminio (A1C13) . 7. Method according to claim 6, characterized in that the Lewis acid used in step (a) is aluminum chloride (A1C1 3 ).
8. Procedimiento según la reivindicaciones 4, 5, 6 ó 7, caracterizado porque la reacción de acilación de Friedel- Crafts con el ácido de Lewis la etapa (a) se efectúa a reflujo. Method according to claims 4, 5, 6 or 7, characterized in that the Friedel-Crafts acylation reaction with Lewis acid step (a) is carried out under reflux.
9. Procedimiento según cualquiera de las reivindicaciones 4 a 8, caracterizado porque la base fuerte empleada en la etapa (b) se selecciona entre un hidruro metálico, un hidróxido metálico, un alcóxido metálico, un amiduro metálico, una base orgánica nitrogenada, un acetiluro metálico, una hexametildisilazida metálica y un alquil metal. 9. Method according to any of claims 4 to 8, characterized in that the strong base employed in step (b) is selected from a metal hydride, a metal hydroxide, a metal alkoxide, a metal amide, a nitrogen-based organic base, an acetylide metallic, a metallic hexamethyldisilazide and an alkyl metal.
10. Procedimiento según la reivindicación 9, caracterizado porque la base fuerte empleada en la etapa (b) es etóxido de sodio. 10. Method according to claim 9, characterized in that the strong base used in step (b) is sodium ethoxide.
11. Procedimiento según reivindicaciones 9 ó 10, caracterizado porque la reacción con la base fuerte de la etapa (b) se efectúa a reflujo. 11. Method according to claims 9 or 10, characterized in that the reaction with the strong base of step (b) is carried out at reflux.
12. Procedimiento según cualquiera de las reivindicaciones 4 a 11, caracterizado porque el ácido empleado en la etapa (c) se selecciona entre ácido clorhídrico (HC1) , ácido sulfúrico (H2S0 ) , ácido nítrico (HN03) o ácido fosfórico (H3P04) , preferentemente, ácido clorhídrico (HC1) Method according to any one of claims 4 to 11, characterized in that the acid used in step (c) is selected from hydrochloric acid (HC1), sulfuric acid (H 2 S0), nitric acid (HN0 3 ) or phosphoric acid ( H 3 P0 4 ), preferably, hydrochloric acid (HC1)
13. Composición farmacéutica que comprende un compuesto deuterado de fórmula (I) y, al menos, un excipiente farmacéuticamente aceptable. 13. Pharmaceutical composition comprising a deuterated compound of formula (I) and at least one pharmaceutically acceptable excipient.
14. Uso del compuesto deuterado de fórmula (I) para la fabricación de un medicamento para el tratamiento del hipertiroidismo . 14. Use of the deuterated compound of formula (I) for the manufacture of a medicament for the treatment of hyperthyroidism.
15. Uso del compuesto deuterado de fórmula (I) definido en las reivindicaciones 1-3 como patrón para la detección de un compuesto de fórmula (II) 15. Use of the deuterated compound of formula (I) defined in claims 1-3 as a standard for the detection of a compound of formula (II)
Figure imgf000015_0001
Figure imgf000015_0001
en la que Ri, R2 y R3 tienen los significados dados en la reivindicación 1. wherein Ri, R 2 and R 3 have the meanings given in claim 1.
PCT/ES2011/000361 2010-12-07 2011-12-07 Deuterated phenacyl and derivatives, method for the preparation thereof and uses thereof WO2012076736A1 (en)

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US8841314B2 (en) 2011-11-11 2014-09-23 Pfizer Inc. 2-Thiopyrimidinones
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