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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. S-Enantiomer einer Verbindung der Formel I worin R1 für 2,4-Difluorphenyl oder Cyclohexyl steht, und pharmazeutisch annehmbare Salze, Solvate, kristalline Formen und
    - C1-6-Alkoxymethylester,
    - C1-6-Alkanoyloxymethylester,
    - Phthalidylester;
    - C3-8Cycloalkoxycarbonyloxy-C1-6-alkylester,
    - 1,3-Dioxolen-2-onylmethylester und
    - C1-6-Alkoxycarbonyloxyethylester.
  2. Verbindung, ausgewählt unter:
    (2S)-3-(4-{2-[(Cyclohexylmethyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropansäure und
    (25)-3-(4-{2-[(2,4-Difluorbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropansäure
    und pharmazeutisch annehmbaren Salzen, Solvaten und kristallinen Formen davon.
  3. (2S)-3-(4-{2-[(Cyclohexylmethyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropansäure und pharmazeutisch annehmbare Salze, Solvate und kristalline Formen davon.
  4. (2S)-3-(4-{2-[(2,4-Difluorbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropansäure und pharmazeutisch annehmbare Salze, Solvate und kristalline Formen davon.
  5. Pharmazeutische Zusammensetzung, enthaltend eine Verbindung nach einem der Ansprüche 1-4 in Abmischung mit pharmazeutisch annehmbaren Hilfsstoffen, Verdünnungsmitteln und/oder Trägern.
  6. Verwendung einer Verbindung nach einem der Ansprüche 1-4 bei der Herstellung eines Arzneimittels zur Behandlung von Lipidstörungen (Dyslipidämie), ob mit Insulinresistenz assoziiert oder nicht.
  7. Verwendung einer Verbindung nach einem der Ansprüche 1-4 bei der Herstellung eines Arzneimittels zur Behandlung oder Prävention von Diabetes Typ 2.
  8. Verfahren zur Herstellung einer Verbindung der Formel I, bei dem man eine Verbindung der Formel II worin R1 die in Anspruch 1 angegebene Bedeutung besitzt und R2 für eine Schutzgruppe für eine Carbonsäure-Hydroxylgruppe steht, mit einem Entschützungsmittel umsetzt.
  9. Verbindung der Formel II worin R1 die in Anspruch 1 angegebene Bedeutung besitzt und R2 für eine Schutzgruppe für eine Carbonsäure-Hydroxylgruppe steht.
  10. Verbindung der Formel III worin R2 die in Anspruch 8 angegebene Bedeutung besitzt.
  11. Pharmazeutische Zusammensetzung, enthaltend eine Verbindung nach einem der Ansprüche 1-4 in Kombination mit einem anderen Therapeutikum, das zur Verwendung bei der Behandlung von Erkrankungen, die mit der Entwicklung und dem Fortschreiten von Atherosklerose, Hyperlipidämien, Dyslipidämien, Diabetes und Adipositas assoziiert sind, geeignet ist.
  12. Pharmazeutische Zusammensetzung, enthaltend eine Verbindung nach einem der Ansprüche 1-4 in Kombination mit einem anderen PPAR-Modulator.
  13. Pharmazeutische Zusammensetzung, enthaltend eine Verbindung nach einem der Ansprüche 1-4 in Kombination mit einem Cholesterinsenker.
  14. Pharmazeutische Zusammensetzung, enthaltend eine Verbindung nach einem der Ansprüche 1-4 in Kombination mit einem HMG-CoA-Reduktase-Inhibitor.
  15. Pharmazeutische Zusammensetzung, enthaltend eine Verbindung nach einem der Ansprüche 1-4 in Kombination mit Atorvastatin oder einem pharmazeutisch annehmbaren Salz, einem pharmazeutisch annehmbaren Solvat oder einer pharmazeutisch annehmbaren kristallinen Form davon.
  16. Pharmazeutische Zusammensetzung, enthaltend eine Verbindung nach einem der Ansprüche 1-4 in Kombination mit Rosuvastatin oder einem pharmazeutisch annehmbaren Salz davon.
  17. Pharmazeutische Zusammensetzung, enthaltend eine Verbindung nach einem der Ansprüche 1-4 in Kombination mit einem IBAT-Inhibitor.
  18. Pharmazeutische Zusammensetzung nach Anspruch 17, bei der der IBAT-Inhibitor unter 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]-methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthzo-8-(N-{(R)-1'-phenyl-1'-[N'-(2-sulfoethyl)carbamoyl]-methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(2-sulfoethyl)carbamoyl]-methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-sulfoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-sulfoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-carboxyethyl)carbamoyl]benzyl}-carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl--7-methylthio-8-(N-{(R)-α-[N'-(2-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(5-carboxypentyl)carbamoyl]benzyl)-carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-carboxyethyl}carbamoyl]benzyl}-carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{α-[N'-(2-sulfoethyl)carbamoyl]-2-fluorbenzyl}-carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3--butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(R)-(2-hydroxy-l-carboxyethyl)-carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(R)-(2-hydroxy-1-carboxyethyl)-carbamoyllbenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-[(R)-α-(N'-{(R)-1-[N"-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]-2-hydroxyethyl}carbamoyl)benzyl]-carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N'-(carboxymethyl)carbamoyl]benzyl}-carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N'-((ethoxy)(methyl)phosphorylmethyl)-carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[(hydroxy)(methyl)phosphoryl]-ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N'-(2-methylthio-1-carboxyethyl)-carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthin-8-{N-[(R)-α-(N'-{2-[(methyl)(ethyl)phosphoryl)ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N'-{2-[(methyl)(hydroxy)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(R)-N'-(2-methylsulfinyl-1-carboxyethyl)-carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N-{(R)-α-[N'-(2-sulfoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8- (N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)-carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)-carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)-carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Diaxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]benzyl}-carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]benzyl}-carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-(R)-hydroxypropyl)-carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulfoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((R)-1-carboxy-2-methylthioethyl)-carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxy-2-methylpropyl)-carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benaothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-(N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R/S)-α-{N-[1-(R)-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2-yl]carbamoyl}-4-hydroxybenzyl)carbamoymethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin; 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-4-hydroxybenzyl}-carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin und 1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-(S)-3-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin oder einem pharmazeutisch annehmbaren Salz, Solvat, Solvat eines derartigen Salzes oder
    - C1-6-Alkoxymethylestern
    - C1-6-Alkanoyloxymethylestern,
    - Phthalidylestern;
    - C3-8-Cycloalkoxycarbonyloxy-C1-6-alkylestern,
    - 1,3-Dioxolen-2-onylmethylestern und
    - C1-6-Alkoxycarbonyloxyethylestern
    ausgewählt ist.
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 (en) 2001-12-19 2002-12-18 Substituted phenylpropionic acid derivatives as agonists to human peroxisome proliferator-activated receptor alpha (ppar)

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