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HK1068870A1 - Substituted phenylpropionic acid derivatives as agonists to human peroxisome proliferator-activated receptor alpha (ppar) - Google Patents

Substituted phenylpropionic acid derivatives as agonists to human peroxisome proliferator-activated receptor alpha (ppar) Download PDF

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HK1068870A1
HK1068870A1 HK05101304A HK05101304A HK1068870A1 HK 1068870 A1 HK1068870 A1 HK 1068870A1 HK 05101304 A HK05101304 A HK 05101304A HK 05101304 A HK05101304 A HK 05101304A HK 1068870 A1 HK1068870 A1 HK 1068870A1
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phenyl
methylthio
carbamoyl
tetrahydro
carbamoylmethoxy
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HK1068870B (en
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Eva-Lotte Alstermark Lindstedt
Anna Christina Olsson
Lanna Li
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Astrazeneca Ab
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Claims (18)

  1. Enantiomère S d'un composé de formule 1 dans laquelle R1 représente un groupe 2,4-difluorophényle ou un groupe cyclohexyle, et des sels, des solvates, des formes cristallines et
    - des esters C1-6-alcoxyméthyliques,
    - des esters C1-6-alcanoyloxyméthyliques,
    - des esters phtalidyliques,
    - des esters C3-8-cycloalcoxycarbonyloxy-C1-6-alkyliques,
    - des esters 1,3-dioxolén-2-onylméthyliques, et
    - des esters C1-6-alcoxycarbonyloxyéthyliques,
    pharmaceutiquement acceptables.
  2. Composé choisi parmi:
    l'acide (2S)-3-(4-{2-[(cyclohexylméthyl)(heptyl)amino]-2-oxoéthoxy)phényl) -2-éthoxypropanoïque ; et
    l'acide (2S)-3-(4-{2-[(2,4-difluorobenzyl)(heptyl) amino]-2-oxoéthoxy}phényl)-2-éthoxypropanoïque et des sels, des solvates et des formes cristallines pharmaceutiquement acceptables de celui-ci.
  3. Acide (2S)-3-(4-{2-[(cyclohexylméthyl)(heptyl)amino]-2-oxoéthoxy}phényl)-2-éthoxypropanoïque et des sels, des solvates et des formes cristallines pharmaceutiquement acceptables de celui-ci.
  4. Acide (2S)-3-(4-{2-[(2,4-difluorobenzyl)(heptyl)amino]-2-oxoéthoxy}phényl}-2-éthoxypropanoique et des sels, des solvates et des formes cristallines pharmaceutiquement acceptables de celui-ci.
  5. Formulation pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 4 en mélange avec des adjuvants, des diluants et/ou des supports pharmaceutiquement acceptables.
  6. Utilisation d'un composé selon l'une quelconque des revendications 1 à 4 pour la fabrication d'un médicament destiné au traitement de troubles lipidiques (dyslipidémie), qu'ils soient associés ou non à une résistance à l'insuline.
  7. Utilisation d'un composé selon l'une quelconque des revendications 1 à 4 pour la fabrication d'un médicament destiné au traitement ou à la prévention du diabète de type 2.
  8. Procédé de préparation d'un composé de formule I, comprenant la réaction d'un composé de formule II dans laquelle R1 est tel que défini dans la revendication 1 et R2 représente un groupe protecteur pour un groupe hydroxycarboxylique, avec un agent de déprotection.
  9. Composé de formule II dans laquelle R1 est tel que défini dans la revendication 1 et R2 représente un groupe protecteur pour un groupe hydroxycarboxylique.
  10. Composé de formule III dans laquelle R2 est tel que défini dans la revendication 8.
  11. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 4, combiné avec un autre agent thérapeutique qui est utile pour le traitement de troubles associés au développement et à l'évolution de l'athérosclérose, tels que l'hypertension, des hyperlipidémies, des dyslipidémies, le diabète et l'obésité.
  12. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 4, combiné avec un autre agent de modulation de PPAR.
  13. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 4, combiné avec un agent hypocholestérolémiant.
  14. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 4, combiné avec un inhibiteur de HMG-CoA réductase.
  15. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 4, combiné avec de l'atorvastatine ou un sel, un solvate ou une forme cristalline pharmaceutiquement acceptable de celle-ci.
  16. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 4, combiné avec de la rosuvastatine ou un sel pharmaceutiquement acceptable de celle-ci.
  17. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 4, combiné avec un inhibiteur d'IBAT.
  18. Composition pharmaceutique selon la revendication 18, dans laquelle l'inhibiteur d'IBAT est choisi parmi :
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-1'-phényl-1'-[N'-(carboxyméthyl)carbamoyl]méthyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N'-(carboxyméthyl)carbamoyl]-4-hydroxybenzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-1'-phényl-1'-[N'-(2-sulfoéthyl)carbamoyl]méthyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine ;
    la 1,1-dioxo-3-butyl-3-éthyl-5-phényl-7-méthylthio-8-(N-((R)-1'-phényl-1'-[N'-(2-sulfoéthyl)carbamoyl]méthyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N'-(2-sulfoéthyl)carbamoyl]-4-hydroxybenzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine ;
    la 1,1-dioxo-3-butyl-3-éthyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N'-(2-sulfoéthyl)carbamoyl]-4-hydroxybenzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine ;
    la 1,1-dioxo-3-butyl-3-éthyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N'-(2-carboxyéthyl)carbamoyl]benzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N'-(2-carboxyéthyl)carbamoyl]-4-hydroxybenzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine ;
    la 1,1-dioxo-3-butyl-3-éthyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N'-(5-carboxypentyl)carbamoyl]benzyl)carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N'-(2-carboxyéthyl)carbamoyl]benzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{α-[N'-(2-sulfoéthyl)carbamoyl]-2-fluorobenzyl)carbamoylmtéhoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine;
    la 1,1-dioxo-3-butyl-3-éthyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N'-(R)-(2-hydroxy-1-carboxyéthyl)carbamoyl]benzyl}carbamoylméthoxy}-2,3,4,5-tétrahydro-1,5-benzothiazépine;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N'-(R)-(2-hydroxy-1-carboxyéthyl)carbamoyl]benzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-{N-[(R)-α-(N'-{(R)-1-[N"-(R)-(2-hydroxy-1-carboxyéthyl)carbamoyl]-2-hydroxyéthyl}carbamoyl)benzyl]carbamoylméthoxy}-2,3,4,5-tétrahydro-1,5-benzothiazépine;
    la 1,1-dioxo-3-butyl-3-éthyl-5-phényl-7-méthylthio-8-(N-{α-[N'-(carboxyméthyl)carbamoyl]benzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine;
    la 1,1-dioxo-3-butyl-3-éthyl-5-phényl-7-méthylthio-8-(N-{α-[N'-((éthoxy)(méthyl)phosphorylméthyl)carbamoyl]benzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine;
    la 1,1-dioxo-3-butyl-3-éthyl-5-phényl-7-méthylthio-8-{N-[(R)-α-(N'-{2-[(hydroxy)(méthyl)phosphoryl]éthyl}carbamoyl)benzyl] carbamoylméthoxy}-2,3,4,5-tétrahydro-1,5-benzothiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N'-(2-méthylthio-1-earboxyéthyl)carbamoyl]benzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-{N-[(R}-α-(N'-{2-[(méthyl}(éthyl)phosphoryl]éthyl}carbamoyl)-4-hydroxybezxzyl]carbamoylméthoxy}-2,3,4,5-tétrahydro-1,5-benzothiazépine ; la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-{N-[(R)-α-(N'-{2-[(méthyl)(hydroxy)phosphoryl]éthyl}carbamoyl)-4-hydroxybenzyl]carbamoylméthoxy}-2,3,4,5-tétrahydro-1,5-benzothiazépine; la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[(R)-N'-(2-méthylsulfinyl-1-carboxyéthyl)carbamoyl]benzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,5-benzothiazépine;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthoxy-8-[N-{(R)-α-[N'-(2-sulfoéthyl)carbamoyl]-4-hydroxybenzyl}carbamoylméthoxy]-2,3,4,5-tétrahydro-1,5-benzothiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-méthylthioéthyl)carbamoyl]-4-hydroxybenzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl)carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-méthylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-((S)-1-carboxyéthyl)carbamoyl]benzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)caxbamoyl]benzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-(2-sulfoéthyl)carbamoyl]-4-hydroxybenzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-((S)-1-carboxyéthyl)carbamoyl]-4-hydroxybenzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-méthylthioéthyl)carbamoyl]benzyl}carbamoylméthoxy} -2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyéthyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-méthylpropyl)carbamoyl]benzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine ;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-[N-((R/S)-α-{N-[1-(R)-2-(S)-1-hydroxy-1-(3,4-dihydroxyphényl)prop-2-yl]carbamoyl}-4-hydroxybenzyl}carbamoylméthoxy]-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine;
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl}carbamoyl]-4-hydroxybenzyl}carbamoylméthoxy)-2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine ; et
    la 1,1-dioxo-3,3-dibutyl-5-phényl-7-méthylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylméthoxy) -2,3,4,5-tétrahydro-1,2,5-benzothiadiazépine;
    ou un sel, un solvate, un solvate d'un tel sel ou
    - des esters C1-6-alcoxyméthyliques,
    - des esters C1-6-alcanoyloxyméthyliques,
    - des esters phtalidyliques,
    - des esters C3-8-cycloalcoxycarbonyloxy-C1-6-alkyliques,
    - des esters 1,3-dioxolén-2-onylméthyliques, et
    - des esters C1-6-alcoxycarbonyloxyéthyliques,
    pharmaceutiquement acceptables.
HK05101304.4A 2001-12-19 2002-12-18 Substituted phenylpropionic acid derivatives as agonists to human peroxisome proliferator-activated receptor alpha (ppar) HK1068870B (en)

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SE0104334A SE0104334D0 (sv) 2001-12-19 2001-12-19 Therapeutic agents
SE0104334 2001-12-19
PCT/GB2002/005744 WO2003051822A1 (fr) 2001-12-19 2002-12-18 Derives d'acide phenylpropionique comme antagonistes de recepteur alpha active par proliferateur de peroxisome humain (ppar)

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HK1068870A1 true HK1068870A1 (en) 2005-05-06
HK1068870B HK1068870B (en) 2007-10-26

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