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HK1110579A1 - New histone deacetylases inhibitors - Google Patents

New histone deacetylases inhibitors Download PDF

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Publication number
HK1110579A1
HK1110579A1 HK08101191.7A HK08101191A HK1110579A1 HK 1110579 A1 HK1110579 A1 HK 1110579A1 HK 08101191 A HK08101191 A HK 08101191A HK 1110579 A1 HK1110579 A1 HK 1110579A1
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HK
Hong Kong
Prior art keywords
phenyl
hydroxy
propenyl
oxo
acrylamide
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HK08101191.7A
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German (de)
English (en)
Chinese (zh)
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HK1110579B (en
Inventor
Saverio Minucci
Pier Giuseppe Pelicci
Antonello Mai
Marco Ballarini
Gaetano Gargiulo
Silvio Massa
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Genextra S.P.A.
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Publication of HK1110579A1 publication Critical patent/HK1110579A1/en
Publication of HK1110579B publication Critical patent/HK1110579B/en

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Claims (20)

  1. Composé de formule (I) dans laquelle R3 est choisi parmi un atome d'hydrogène, un groupe alcoxyalkyle ; Ar est un groupe aryle ou hétéroaryle éventuellement substitué, A est choisi parmi où R2 est choisi parmi les groupes hydrogéno, alkyle, cycloalkyle, aryle, arylalkyle, hétérocyclyle, hétérocyclyl-alkyle, halogéno, halogénoalkyle, hydroxy, hydroxyalkyle, alcoxy, halogénoalcoxy, amino, aminoalkyle, alkylamino, (thio)carbonylamino, (thio)aminocarbonyle, sulfonylamino, aminosulfonyle, (thio)acyle, (thio)acyloxy, (thio)alcoxycarbonyle, nitro et nitrile ; R1 est choisi parmi où Y représente 0, S, NH, CH2, NOH ou NOR5, où R5 est un groupe alkyle ayant de 1 à 4 atomes de carbone.
  2. Composé selon la revendication 1, dans lequel Ar est choisi parmi les groupes phényle, naphtyle, pyridyle, pyranyle, pyrrolyle, thiényle, furanyle, benzofuranyle, benzothiényle, indolyle, éventuellement substitués.
  3. Composé selon les revendications 1 à 2, dans lequel Ar est substitué par un ou plusieurs des groupes halogéno, hydroxy, alkyle, alcoxy, trifluoroalkyle, trifluoroalcoxy, dialkylamino, morpholyle, pipérazinyle, métoxycarbonyle.
  4. Composé selon les revendications 1 à 3, dans lequel le groupe R1 et le groupe contenant R3 sont liés l'un à l'autre en relation para sur le cycle A.
  5. Composé selon les revendications 1 à 4, dans lequel R2 est choisi parmi les groupes hydrogéno, halogéno, alkyle, alcoxy.
  6. Composé selon les revendications 1 à 5, dans lequel R3 est un atome d'hydrogène.
  7. Composé selon les revendications 1 à 6, ayant l'une des structures suivantes : dans lesquelles Ar et R2 ont les significations mentionnées précédemment, et X est un atome de carbone ou d'azote.
  8. Composé selon la revendication 7, dans lequel dans les formules (IA-d), X est un atome de carbone, R2 est un atome d'hydrogène et Ar est choisi parmi les groupes : phényle, 2-chlorophényle, 3-chlorophényle, 4-chlorophényle, 2-fluorophényle, 3-fluorophényle, 4-fluorophényle, 2-méthylphényle, 3-méthylphényle, 4-méthylphényle, 1-naphtyle, 5-dihydrobenzofuryle.
  9. Composé selon la revendication 1, choisi parmi les :
    3-[3-fluoro-4-(3-oxo-3-phényl-propényl)-phényl]-N-hydroxy-acrylamide ;
    3-[3-chloro-4-(3-oxo-3-phényl-propényl)-phényl]-N-hydroxy-acrylamide ;
    3-[3-chloro-4-(3-oxo-3-o-tolyl-propényl)-phényl]-N-hydroxy-acrylamide ;
    3-{3-chloro-4-[3-(2-méthoxy-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-{3-chloro-4-[3-(2-fluoro-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-{3-chloro-4-[3-(2-chloro-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-[3-chloro-4-(3-oxo-3-m-tolyl-propényl)-phényl]-N-hydroxy-acrylamide ;
    3-{3-chloro-4-[3-(3-méthoxy-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-{3-chloro-4-[3-(3-fluoro-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-{3-chloro-4-[3-(3-chloro-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-[3-chloro-4-(3-oxo-3-p-tolyl-propényl)-phényl]-N-hydroxy-acrylamide ;
    3-{3-chloro-4-[3-(4-méthoxy-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-{3-chloro-4-[3-(4-fluoro-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-{3-chloro-4-[3-(4-chloro-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-[3-chloro-4-(3-oxo-3-thiophén-2-yl-propényl)-phényl]-N-hydroxy-acrylamide ;
    3-[3-fluoro-4-(3-oxo-3-o-tolyl-propényl)-phényl]-N-hydroxy-acrylamide ;
    3-{3-fluoro-4-[3-(2-méthoxy-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-{3-fluoro-4-[3-(2-fluoro-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-(4-[3-(2-chloro-phényl)-3-oxo-propényl]-3-fluoro-phényl}-N-hydroxy-acrylamide ;
    3-[3-fluoro-4-(3-oxo-3-m-tolyl-propényl)-phényl]-N-hydroxy-acrylamide ;
    3-{3-fluoro-4-[3-(3-méthoxy-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-(3-fluoro-4-[3-(3-fluoro-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-{4-[3-(3-chloro-phényl)-3-oxo-propényl]-3-fluoro-phényl}-N-hydroxy-acrylamide ;
    3-[3-fluoro-4-(3-oxo-3-p-tolyl-propényl)-phényl]-N-hydroxy-acrylamide ;
    3-{3-fluoro-4-[3-(4-méthoxy-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-{3-fluoro-4-[3-(4-fluoro-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    3-{4-[3-(4-chloro-phényl)-3-oxo-propényl]-3-fluoro-phényl}-N-hydroxy-acrylamide ;
    3-[3-fluoro-4-(3-oxo-3-thiophén-2-yl-propényl)-phényl]-N-hydroxy-acrylamide ;
    3-{3-fluoro-4-[3-(4-morpholin-4-yl-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    N-hydroxy-3-{4-[3-(2-méthoxy-phényl)-3-oxo-propényl]-phényl}-acrylamide ;
    N-hydroxy-3-{4-[3-oxo-3-(2-trifluorométhyl-phényl)-propényl]-phényl}-acrylamide ;
    N-hydroxy-3-{4-[3-oxo-3-(2-trifluorométhoxy-phényl)-propényl]-phényl}-acrylamide ;
    3-{4-[3-(2-bromo-phényl)-3-oxo-propényl]phényl}-N-hydroxy-acrylamide ;
    N-hydroxy-3-{4-[3-(3-méthoxy-phényl)-3-oxo-propényl]-phényl}-acrylamide ;
    3-{4-[3-(3-bromo-phényl)-3-oxo-propényl]-phényl}-N-hydroxy-acrylamide ;
    N-hydroxy-3-{4-[3-(4-méthoxy-phényl)-3-oxo-propényl]-phényl}-acrylamide ;
    N-hydroxy-3-{4-[3-oxo-3-(4-trifluorométhyl-phényl)-propényl]-phényl}-acrylamide ;
    N-hydroxy-3-{4-[3-oxo-3-(4-trifluorométhoxy-phényl)-propényl]-phényl}-acrylamide ;
    3-{4-[3-(4-bromo-phényl)-3-oxo-propényl]phényl}-N-hydroxy-acrylamide ;
    3-{4-[3-(4-diéthylamino-phényl)-3-oxo-propényl]phényl}-N-hydroxy-acrylamide ;
    N-hydroxy-3-{4-[3-(4-morpholin-4-yl-phényl)-3-oxo-propényl]-phényl}-acrylamide ;
    3-[4-(3-furan-2-yl-3-oxo-propényl)phényl]-N-hydroxy-acrylamide ;
    N-hydroxy-3-[4-(3-oxo-3-thiophén-2-yl-propényl)-phényl]-acrylamide ;
    N-hydroxy-3-{4-[3-oxo-3-(1H-pyrrol-2-yl)-propényl]-phényl}-acrylamide ;
    3-[4-(3-benzofuran-2-yl-3-oxo-propényl)phényl]-N-hydroxy-acrylamide ;
    3-[4-(3-benzo[b]thiophén-2-yl-3-oxo-propényl)-phényl]-N-hydroxy-acrylamide ;
    N-hydroxy-3-[4-(3-oxo-3-thiophén-3-yl-propényl)-phényl]-acrylamide ;
    N-hydroxy-3-{4-[3-(3-méthoxy-4-morpholin-4-ylméthyl-phényl)-3-oxo-propényl]-phényl}-acrylamide ;
    3-{4-[3-(3,4-difluoro-phényl)-3-oxo-propényl] phényl}-N-hydroxy-acrylamide ;
    3-{4-[3-(3,5-difluoro-phényl)-3-oxo-propényl] phényl}-N-hydroxy-acrylamide ;
    3-{4-[3-(2,5-difluoro-phényl)-3-oxo-propényl] phényl}-N-hydroxy-acrylamide ;
    3-{4-[3-(2,6-difluoro-phényl)-3-oxo-propényl] phényl}-N-hydroxy-acrylamide ;
    N-hydroxy-3-[3-méthoxy-4-(3-oxo-3-thiophén-2-yl-propényl)-phényl]-acrylamide ;
    N-hydroxy-3-[3-méthyl-4-(3-oxo-3-thiophén-2-yl-propényl)-phényl]-acrylamide ;
    ester méthylique d'acide 4-{3-[4-(2-hydroxycarbamoyl-vinyl)-phényl]-acryloyl}-benzoique ;
    ester méthylique d'acide 3-{3-[4-(2-hydroxycarbamoyl-vinyl)-phényl]-acryloyl}-benzoïque ;
    3-{4-[3-(5-chloro-thiophén-2-yl)-3-oxo-propényl] phényl}-N-hydroxy-acrylamide ;
    N-hydroxy-3-{4-[3-(3-hydroxy-phényl)-3-oxo-propényl]-phényl}-acrylamide ;
    N-hydroxy-3-(4-{3-[4-(4-méthyl-pipérazin-1-yl)-phényl]-3-oxo-propényl}-phényl)-acrylamide ;
    N-hydroxy-3-[2-méthoxy-4-(3-oxo-3-phényl-propényl)phényl]-acrylamide ;
    3-[2-fluoro-4-(3-oxo-3-phényl-propényl)-phényl]-N-hydroxy-acrylamide ;
    3-[2-chloro-4-(3-oxo-3-phényl-propényl)-phényl]-N-hydroxy-acrylamide ;
    N-hydroxy-3-[4-(3-oxo-3-pyridin-3-yl-propényl)-phényl]-acrylamide ;
    N-hydroxy-3-[4-(3-oxo-3-pyridin-2-yl-propényl)-phényl]-acrylamide ;
    N-hydroxy-3-[4-(3-oxo-3-pyridin-4-yl-propényl)-phényl]-acrylamide ;
    N-hydroxy-3-[3-méthyl-4-(3-oxo-3-phényl-propényl)-phényl]-acrylamide ;
    N-hydroxy-3-[3-méthoxy-4-(3-oxo-3-phényl-propényl)-phényl]-acrylamide ;
    3-[3-fluoro-4-(3-oxo-3-pyridin-3-yl-propényl)-phényl]-N-hydroxy-acrylamide ;
    N-hydroxy-3-[5-(3-oxo-3-phényl-propényl)-pyridin-2-yl]-acrylamide ;
    N-hydroxy-3-{5-[3-(2-méthoxy-phényl)-3-oxo-propényl]-pyridin-2-yl}-acrylamide ;
    N-hydroxy-3-[5-(3-oxo-3-thiophén-2-yl-propényl)-pyridin-2-yl]-acrylamide ;
    3-{5-[3-(3,4-difluoro-phényl)-3-oxo-propényl]-pyridin-2-yl}-N-hydroxy-acrylamide.
  10. Procédé de préparation des composés de formule (I), comprenant le traitement d'un composé de formule (II) dans laquelle A et R2 ont les significations mentionnées précédemment et R4 est un groupe partant approprié,
    (i) ayant un composé de formule Ar-W, où Ar a les significations mentionnées précédemment et W est un groupe pouvant former, par réaction avec le groupe CHO de (II), le groupe R1 tel que défini ci-dessus, ou un intermédiaire de synthèse de celui-ci
    (ii) et en outre avec un composé de formule (III)
    dans laquelle Z représente NHOR3 tel que défini ci-dessus ou un précurseur de celui-ci.
  11. Procédé selon la revendication 10, dans lequel le composé Ar-W est une acétophénone éventuellement substituée sur le cycle phényle.
  12. Procédé selon les revendications 10 à 11, dans lequel la réaction d'addition d'un composé Ar-W s'effectue dans un environnement alcalin.
  13. Procédé selon les revendications 10 à 12, dans lequel le composé de formule (III) est un alkylacrylate.
  14. Procédé selon les revendications 10 à 13, dans lequel le composé de formule (III) est un n-butylacrylate.
  15. Procédé selon les revendications 10 à 14, dans lequel la réaction d'addition du composé de formule (III) s'effectue en présence de phosphate de potassium et d'acétate de palladium.
  16. Composé de formule (I) tel que défini dans les revendications 1 à 9, à utiliser en traitement.
  17. Composition pharmaceutique caractérisée en ce qu'elle comprend un ou plusieurs principes actifs de formule (I) tels que définis dans les revendications 1 à 9, en association avec des excipients et diluants pharmaceutiquement acceptables.
  18. Composition selon la revendication 17, utile pour l'administration orale ou parentérale sous la forme de comprimés, de capsules, de préparations orales, de poudres, de granulés, de pastilles, de poudres à reconstituer, de solutions ou suspensions liquides injectables ou perfusables, de suppositoires, de suspensions, solutions, émulsions, sirops, élixirs aqueux ou huileux ou sous la forme d'une composition transdermique.
  19. Composition selon la revendication 17, utile pour l'utilisation topique sous la forme de pommade, de crème, de gel, de lotion, de solution, de pâte ou autre, contenant éventuellement des liposomes, des micelles et/ou des microsphères.
  20. Utilisation d'un ou plusieurs composés de formule (I) tels que définis selon les revendications 1 à 9, dans la préparation d'un médicament pour la prévention et/ou le traitement de maladies associées à la dérégulation de l'activité des histones désacétylases
HK08101191.7A 2004-10-01 2005-09-30 New histone deacetylases inhibitors HK1110579B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITMI2004A001869 2004-10-01
IT001869A ITMI20041869A1 (it) 2004-10-01 2004-10-01 Nuovi inibitori delle istone deacetilasi
PCT/EP2005/054949 WO2006037761A1 (fr) 2004-10-01 2005-09-30 Nouveaux inhibiteurs des histone-deacetylases

Publications (2)

Publication Number Publication Date
HK1110579A1 true HK1110579A1 (en) 2008-07-18
HK1110579B HK1110579B (en) 2014-03-21

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CA2581730A1 (fr) 2006-04-13
ITMI20041869A1 (it) 2005-01-01
IL182237A0 (en) 2007-09-20
IL182237A (en) 2012-03-29
KR101191558B1 (ko) 2012-10-15
ZA200703390B (en) 2008-10-29
KR20070070179A (ko) 2007-07-03
ES2428539T9 (es) 2015-09-15
NZ554640A (en) 2009-09-25
WO2006037761A1 (fr) 2006-04-13
PL1814850T3 (pl) 2013-12-31
US8058273B2 (en) 2011-11-15
EP1814850B1 (fr) 2013-07-03
ES2428539T3 (es) 2013-11-08
CA2581730C (fr) 2012-10-30
EP1814850B9 (fr) 2015-02-25
US7803800B2 (en) 2010-09-28
JP4979583B2 (ja) 2012-07-18
RU2007116098A (ru) 2008-11-10
AU2005291297A1 (en) 2006-04-13
US20100240660A1 (en) 2010-09-23
EP1814850A1 (fr) 2007-08-08
CN101039905B (zh) 2012-02-08
MX2007003641A (es) 2007-08-14
JP2008514682A (ja) 2008-05-08
US20080096889A1 (en) 2008-04-24
AU2005291297B2 (en) 2010-12-23
CN101039905A (zh) 2007-09-19

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