DK2731676T3 - Nye FXR (NR1H4) modulerende forbindelser - Google Patents

Nye FXR (NR1H4) modulerende forbindelser Download PDF

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DK2731676T3
DK2731676T3 DK12735100.5T DK12735100T DK2731676T3 DK 2731676 T3 DK2731676 T3 DK 2731676T3 DK 12735100 T DK12735100 T DK 12735100T DK 2731676 T3 DK2731676 T3 DK 2731676T3
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liver
alkyl
fxr
disease
compound
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Olaf Kinzel
Christoph Steeneck
Claus Kremoser
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Gilead Sciences Inc
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • 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
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Claims (15)

  1. PATENTlRAV i. Forbindelse ifølge følgende formel (1), en enantiomer, diastereomer, tautomer eller farmaceutisk acceptabelt salt deraf
    (1) hvor R er valgt blandt gruppen bestående af COOR6, CONR7R8, tetrazolyl, SO2NR7R8, G1-6 alkyl, S02-Ci-S alky! og H, hvor R6 uafhængigt er valgt llånlt gruppen bestående af H efter C^alkyl, og R7 og R8 uafhængigt af hinanden er valgt blandt gruppen bestående af H, Chalky!, ha!o-Gi-6 alkyl, Gi_6 alkylen-Rg, 8O2-C1-6 alkyl, hvor Rg er valgt blandt gruppen bestående afCQØH, ØH og SO3H; A er valgt blandt gruppen bestående af phenyl, pyridyl, py rim idyl, pyrazolyl, inddlyl, thienyl, benzothienyl, indazplyl, benzisoxazolyl, benzofuranyi, benzotriazoSyl, furanyl, benzothiazolyl, thiazolyl, oxadiazolyl, hvor hver især valgfrit er substitueret med en eller to grupper, der uafhængigt er valgt blandt gruppen bestående af OH, O-G1.6 alkyl, O-halo-G1-6 alkyl, Ci_6 alkyl, halo-Ci-s alkyl, C3-6 cycloalky! og halogen; 0 er valgt blandt gruppen bestående af phenyl, pyridyl, thiazolyl thiophenyl, pyrirnidfl, hvor hver især valgfrit er substitueret med en eller to grupper, der uafhænfiit er valgt blandt gruppen bestående af C-..Q aikyi halo-åi-6 alkyl, halogen øg GF3; Y er valgt blandt N eller GH; Z er valgt blandt
    hvor X = CH N, NO; Ri er valgt blandt gruppen bestående af hydrogen, G1-3 alkyl, C3.6 cylcoalkyl, G4.5 aikylcycloalkyl, hvor C1.3 alkyl valgfrit er substitueret med 1 til 3 substituenter uafhængigt valgt blandt halogen, hydroxy eller C1-6 alkoxy; R2 og R3 uafhængigt er valgt blandt gruppen bestående af hydrogen, G1.3 alkyl, G1-3 haloalkyl, C1.3 alkoxy, G1.3 haloalkoxy og halogen.
  2. 2. Forbindelse ifølge krav 1, hvor R A er valgt blandt
  3. 3. Forbindelse ifølge krav 1 eller 2, hvor Q er
  4. 4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor Z er
  5. 5. Forbindefse ifølge et hvilket som helst af kravene 1 til 4 valgt blandt
    eller ét farmaceutisk acceptabelt salt deraf.
  6. 6. Forbindelse ifølge ét hvilket som helst af kravene 1 til 5 med følgende struktur
    elleret farmaceutisk acceptabelt salt deraf.
  7. 7, Forbindelse ifølge et hvilket som helst af kravene 1 til 5 med følgende struktur
    eller et farmaceutisk acceptabelt salt dérai
  8. 8. Farmaceutisk sammensætning, der omfatter forbindelsen ifølge et hvilket som Helst af kravene 1 til 7 eller et farmaceutisk acceptabelt salt deraf og ét farmaceutisk acceptabelt bærestof;
  9. 9. Forbindelse ifølge ét hvilket som helst af kravene 1 til 7 til anvendelse som et lægemiddel.
  10. 10. Forbindelse ifølge et hvilket Som helst af kravene 1 til 7 til anvendelse ved profylakse og/eiter behandling af sygdomme medieret af FXR. 11 Forbindelse til anvendelse ifølge krav 10, hvor sygdommen er valgt blandt kronisk intrahepatiske eller nogle former for ekstrahepatisfce eholestatiske tilstande; leverfibrose; obstruktive eller kronisk inflammatonske leverledelser; levercirrose; leversteatose og associerede syndromer, eholestatiske eller fibretiske effekten der er associeret med alkoholfremkaldt eirrose eller med virusbårne former for hepatitis; leversvigt eller iiveriskæmi efter større leverresektion; kemoterapiassocieret steatohepatitlS (CASH, chemotherapy associated steato-hepatitis); akut leversvigt; egfeller inflammatoriske tarmsygdomme;
  11. 12. Forbindelse il anvendelse ifølge krav 10, hvor sygdommen er valgt blandt lipid- og lipoproteinlidelser; type ll-diabetes og kliniske komplikationer fra type I- og type ll-diabetes, inklusive diabetisk nefropati, diabetisk neuropati. diabetisk retinopati og andre observerede effekter af klinisk manifest langvarig diabetes; ilstande og sygdomme, der er et resultat af kronisk fedt- og fibrotisk degeneration af organer som følge af tvangsmæssig lipid- og specielt triglycerldakkumulering og efterfølgende aktivering af profibrotiske eksponeringsveje, såsom ikke-alkoholisk fedÉelersygdom (NAFLD,Non-Alcoholic Fatty Liver Disease) eller ikke-alkoholisk stptøhfpatitis (NASH ,Non-Alcoholic itéatohepatitis); fedme eller metaboisk syndrom (kombinerede tilstande af dyslipidæmi, diabetes eller abnormt løjt kropsmasseindeks); og/elier akut myokardieinfarkt, akut slagtilfælde eller trombose, der optræder som et kronisk endepunkt for kronisk obstruktiv atherosklerose. 13; Forbindelse til anvendelse ifølge krav 10, hvor sygdommen er valgt blandt ikke-maligne hyperproliferative lidelser og maligne hyperproliferative lidelser, specielt blandt hepatocellulær karcinom, colonadenom pg polyposis; adenokarcinom i colon, brystcancer, pancreasadenokarcinom, Barretts øsofagus eller andre former fer neoplastiSke sygdomme i mave-tarmkanalen øg leveren.
  12. 14, Anvendelse af en forbindelse ifølge et hvilket som helst af kravene 1 til 7 til fremstilling af et lægemiddel til profylakse og/etler behandling af sygdomme medieret af FXR,
  13. 15. Anvendelse ifølge krav 14, hvor s|gdommen er valgt ilandt kronisk intrahepatiske eller nogle former for ekstrahepatiske ehoiestatiske tilstande; leverfibrose; obstrukive eller kronisk inflammatoriske leverledelser; levercirrose; leyersteatose og associerede syndromer, ehoiestatiske eller fibrotiske effekter, der er associeret med alkoholfremkaldt cirrose eller med virusbårne former for hepatitis; leversvigt eller liveriskæmi efter større leverresektion; kemøterapiassociéret steatohepatitis (CASH, chemotherapy associated steato-hepatitis); akut leversvigt; og/elfer inflammatoriske tarmsygdomme.
  14. 16. Anvendelse ifølge krav 14, hvor sygdommen er valgt blandf lipid- og iipoprotéinlidelser; type ll-diabetes og kliniske komplikationer fra type I- og type ll-diabetes, inklusive diabetisk nefropati, diabetisk neuropati, diabetisk rélhøpatt og andre observerelO effekter af klinisk manifest langvarig diabetes; tilstande dl sygdomrøf, der er et resultat af kronisk fedt- og fiprotisk degeneration af organer som følge af tvangsmæssig lipid- og specielt trigiyceridakkumulering og efterfølgende aktivering af prøfibrotiske eksponeringsveje, såsom ikke-alkoholisk fedtleversygdom (NAFLC, Non-Alcoholic Fatty Liver Disease) eller ikke-alkoholisk steatohepatitis (NASH, Non-Alcoholic Steatohepatitis); fedme eller metabolsk syndrom (kombinerede tilstande af dyslipidasmi, diabetes eller abnormt højt kropsmasseindeks); og/eller akut mypkardieinfarkt, akut slagtilfælde eller trombose, der optræder søm et kronisk endipunkt før kronisk obstruktiv atherosklerose.
  15. 17. Anvendelse ifølge krav 14, hvor sygdommen er valgt blandt ikke-maligne hyperproliferafive lidelser og maligne hyperproiiferative lidelser, specielt blandt hepatoceilulær karcinom, colonadenom dg polyposis, adenokarcinom i colon, brystcancer pancreasadenokarcinøm, Barretis øsofågus eller andre firmer fdr neoplastiske sygdomme i mavetarmkanalen og leveren.
DK12735100.5T 2011-07-13 2012-07-12 Nye FXR (NR1H4) modulerende forbindelser DK2731676T3 (da)

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US201161507153P 2011-07-13 2011-07-13
EP11005722A EP2545964A1 (en) 2011-07-13 2011-07-13 Novel FXR (NR1H4) binding and activity modulating compounds
PCT/EP2012/002941 WO2013007387A1 (en) 2011-07-13 2012-07-12 Novel fxr (nr1h4) binding and activity modulating compounds

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