WO2012076736A1 - Phénucyle deutéré et dérivés, procédé de préparation et utilisations de ceux-ci - Google Patents

Phénucyle deutéré et dérivés, procédé de préparation et utilisations de ceux-ci Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
group
deuterated
compound
acid
formula
Prior art date
Application number
PCT/ES2011/000361
Other languages
English (en)
Spanish (es)
Inventor
Victor Morales Alcazar
David Arraez Roman
Antonio Segura Carretero
José JUSTICIA LADRON DE GUEVARA
Antonio Rosales Martinez
Juan Enrique Oltra Ferrero
Original Assignee
Universidad De Granada
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universidad De Granada filed Critical Universidad De Granada
Publication of WO2012076736A1 publication Critical patent/WO2012076736A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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)
  • Epidemiology (AREA)
  • 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

L'invention concerne des composés deutérés de formule (I), dans laquelle : R1, R2 et R3 représentent de façon indépendante un atome d'hydrogène ou un groupe alkyle C1-C4, éventuellement substitué par un groupe -OR4; R4 étant un atome d'hydrogène ou un groupe alkyle C1-C3 éventuellement substitué par phényle; un groupe -NR5Re, R5 et Re étant de façon indépendante un atome d'hydrogène, ou un groupe alkyle C1-C3, tosyl ou mésyle; un groupe -SR7, R7 étant un atome d'hydrogène ou un groupe alkyle C1-C3; un groupe -0C0R8, R8 étant un groupe alkyle C1-C3 ou phényle; ou un atome d'halogène; et D représente deutérium. L'invention concerne également un procédé pour préparer lesdits composés deutérés, une composition pharmaceutique qui les comprend, et l'utilisation de ceux-ci dans le domaine pharmaceutique et analytique.
PCT/ES2011/000361 2010-12-07 2011-12-07 Phénucyle deutéré et dérivés, procédé de préparation et utilisations de ceux-ci WO2012076736A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ESP201001572 2010-12-07
ES201001572A ES2352926B1 (es) 2010-12-07 2010-12-07 Fenucil deuterado y derivados, procedimiento para su preparación y usos de los mismos.

Publications (1)

Publication Number Publication Date
WO2012076736A1 true WO2012076736A1 (fr) 2012-06-14

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PCT/ES2011/000361 WO2012076736A1 (fr) 2010-12-07 2011-12-07 Phénucyle deutéré et dérivés, procédé de préparation et utilisations de ceux-ci

Country Status (2)

Country Link
ES (1) ES2352926B1 (fr)
WO (1) WO2012076736A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8835449B2 (en) 2011-11-11 2014-09-16 Pfizer Inc. 2-thiopyrimidinones
US9771332B2 (en) 2015-05-05 2017-09-26 Pfizer Inc. 2-thiopyrimidinones

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
S ABUIN ET AL.: "Analysis of thyreostatic drugs in thyroid samples by liquid chromatography tandem mass spectromatry: comparison of two sample treatment strategies", JOURNAL OF CHROMATOGRAPHY A, vol. 1207, 2008, pages 17 - 23, XP025473775, DOI: doi:10.1016/j.chroma.2008.08.018 *
S ABUIN ET AL.: "Analysis of thyreostatic drugs in thyroid samples by ultra-performance liquid chromatography tandem mass spectrometry detection", ANALYTICAL CHIMICA ACTA, vol. 617, 2008, pages 184 - 191, XP025466855, DOI: doi:10.1016/j.aca.2007.12.018 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8835449B2 (en) 2011-11-11 2014-09-16 Pfizer Inc. 2-thiopyrimidinones
US8841314B2 (en) 2011-11-11 2014-09-23 Pfizer Inc. 2-Thiopyrimidinones
US9399626B2 (en) 2011-11-11 2016-07-26 Pfizer Inc. 2-thiopyrimidinones
US9873673B2 (en) 2011-11-11 2018-01-23 Pfizer Inc. 2-thiopyrimidinones
US9771332B2 (en) 2015-05-05 2017-09-26 Pfizer Inc. 2-thiopyrimidinones

Also Published As

Publication number Publication date
ES2352926A1 (es) 2011-02-24
ES2352926B1 (es) 2012-01-12

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