DK3215498T3 - Hydroxyalkylsubstituerede phenyltriazolderivater og anvendelser deraf - Google Patents

Hydroxyalkylsubstituerede phenyltriazolderivater og anvendelser deraf Download PDF

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DK3215498T3
DK3215498T3 DK15788389.3T DK15788389T DK3215498T3 DK 3215498 T3 DK3215498 T3 DK 3215498T3 DK 15788389 T DK15788389 T DK 15788389T DK 3215498 T3 DK3215498 T3 DK 3215498T3
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triazol
chlorophenyl
methyl
trifluoro
dihydro
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Michael Gerisch
Nils Griebenow
Peter Kolkhof
Florian Kölling
Axel Kretschmer
Dieter Lang
Klemens Lustig
Thomas Mondritzki
Elisabeth Pook
Hartmut Beck
Frank Süssmeier
Sonja Vollmer
Pierre Wasnaire
Carsten Schmeck
Anna Engelen
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Bayer Pharma AG
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    • 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
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Claims (13)

1.2.4- triazol-3-yl]-methyl}-4-[ (2 S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 2-({1-(2-chior-4-fluorphenyl)-5-[(IRS)-1-hydroxyethyl]-1H- 1.2.4- triazol-3-yl}methyl)-5-(4-chlorphenyl)-4-[ (2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 2-{[1-(2-chior-4-fluorphenyl)-5-(1-hydroxyethyl)-lH-l,2,4-triazol-3-yl]methyl}-5-(4-chlorphenyl)-4-[ (2 S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on (diastereomer 1); 2-{ [1- (2-chior-4-fluorphenyl)-5-(1-hydroxyethyl)-lH-l,2,4-triazol-3-yl]methyl}-5-(4-chlorphenyl)-4-[ (2 S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on (diastereomer 2); 2-({1-(2-chlor-5-fluorphenyl)-5-[(IRS)-1-hydroxyethyl]-1H- 1,2,4-triazol-3-yl}methyl)-5-(4-chlorphenyl)-4-[ (2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 2-{ [1- (2-chlor-5-fluorphenyl)-5-(1-hydroxyethyl)-lH-l,2,4-triazol-3-yl]methyl}-5-(4-chlorphenyl)-4-[ (2 S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on (diastereomer 1); 2-{ [1- (2-chlor-5-fluorphenyl)-5-(1-hydroxyethyl)-lH-l,2,4-triazol-3-yl]methyl}-5-(4-chlorphenyl)-4-[ (2 S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on (diastereomer 2); 5- (4-chlorphenyl)-2-({1-(3-fluorphenyl)-5-[ (IRS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[ (2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5- (4-chlorphenyl)-2-({1-(3-fluorphenyl)-5-[ (1R)-1-hydroxyethyl]-lH-l,2,4-triazol-3-yl}-methyl)-4-[(2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5-(4-chlorphenyl)-2-({1-(3-fluorphenyl)-5-[ (IS)-1-hydroxyethyl]-lH-l,2,4-triazol-3-yl}-methyl)-4-[ (2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5-(4-chlorphenyl)-2-({1-(3-chlorphenyl)-5-[(IRS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[ (2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5-(4-chlorphenyl)-2-({1-(3-chlorphenyl)-5-[(1R)-1-hydroxyethyl]-lH-l,2,4-triazol-3-yl}-methyl)-4-[ (2S)-3,3,3- trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5-(4-chlorphenyl)-2-({1-(3-chlorphenyl)-5-[ (IS)-1-hydroxyethyl]-lH-l,2,4-triazol-3-yl}-methyl)-4-[ (2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5-(4-chlorphenyl)-2-({1-(2-chlorphenyl)-5-[(IRS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[ (2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5- (4-chlorphenyl)-2-({1-(2-chlorphenyl)-5-[ (1R)-1-hydroxyethyl]-lH-l,2,4-triazol-3-yl}-methyl)-4-[(2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; og 5-(4-chlorphenyl)-2-({1-(2-chlorphenyl)-5-[ (IS)-1-hydroxyethyl]-lH-l,2,4-triazol-3-yl}-methyl)-4-[(2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l, 2,4-triazol-3-on; eller et farmaceutisk acceptabelt salt, hydrat og/eller solvat deraf .
1. Forbindelse med formel (I)
hvor R1 er hydrogen eller methyl, og R2A og R2B er valgt uafhængigt fra gruppen, der består af hydrogen, fluor, chlor, cyano, methyl, fluormethyl, difluormethyl, trifluormethyl, ethyl, methoxy, difluormethoxy og trifluormethoxy, eller et farmaceutisk acceptabelt salt, hydrat og/eller solvat deraf .
2. Forbindelse med formel (I) ifølge krav 1, hvor R1 er hydrogen eller methyl, og R2A og R2B er valgt uafhængigt fra gruppen, der består af hydrogen, fluor, chlor, methyl og methoxy, hvor mindst én af R2A og R2B er andet end hydrogen, eller et farmaceutisk acceptabelt salt, hydrat og/eller solvat deraf.
3. Forbindelse med formel (I) ifølge krav 1 eller 2, hvor forbindelsen er valgt fra gruppen, der består af 5-(4-chlorphenyl)-2-{[1-(3-chlorphenyl)-5-(hydroxymethyl)-1H- l,2,4-triazol-3-yl]-methyl}-4-[ (2 S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5-(4-chlorphenyl)-2-{[1-(3-fluorphenyl)-5-(hydroxymethyl)-1H- l,2,4-triazol-3-yl]-methyl}-4-[ (2 S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5-(4-chlorphenyl)-2-{[5-(hydroxymethyl)-1-(2-methylphenyl)-IH-
4. Forbindelse med formel (I) ifølge krav 1, 2 eller 3, hvor forbindelsen er valgt fra gruppen, der består af 5-(4-chlorphenyl)-2-({1-(3-fluorphenyl)-5-[(IRS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[ (2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5-(4-chlorphenyl)-2-({1-(3-fluorphenyl)-5-[ (IS)-1-hydroxyethyl]-lH-l,2,4-triazol-3-yl}-methyl)-4-[ (2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5-(4-chlorphenyl)-2-({1-(3-chlorphenyl)-5-[(IRS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[ (2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5-(4-chlorphenyl)-2-({1-(3-chlorphenyl)-5-[ (IS)-1-hydroxyethyl]-lH-l,2,4-triazol-3-yl}-methyl)-4-[(2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; 5- (4-chlorphenyl)-2-({1-(2-chlorphenyl)-5-[ (IRS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[ (2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on; og 5-(4-chlorphenyl)-2-({1-(2-chlorphenyl)-5-[ (IS)-1-hydroxyethyl]-lH-l,2,4-triazol-3-yl}-methyl)-4-[(2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H-l, 2,4-triazol-3-on; eller et farmaceutisk acceptabelt salt, hydrat og/eller solvat deraf.
5. Fremgangsmåde til fremstilling af en forbindelse med formel (I) ifølge kravene 1 til 4, der er kendetegnet ved, at en forbindelse med formel (II)
først reageres med hydrazin til opnåelse af hydrazid med formel (III)
herefter kondenseres med en amidin med formel (IV) eller et salt deraf, hvor R1 har betydningen, der er anført i krav 1 til 4, i nærvær af en base til opnåelse af et 1,2,4-triazolderivat med formel (V)
og/eller en tautomer deraf, hvor R1 har betydningen, der er anført i krav 1 til 4, og efterfølgende kobling med en phenylboronsyre med formel (VI)
(VI), hvor R2A og R2B har betydningerne, der er anført i krav 1 til 4, i nærvær af en kobberkatalysator og en aminbase til opnåelse af målforbindelsen med formel (I)
hvor R1, R2A og R2B har betydningerne, der er anført i krav 1 til 4, eventuelt efterfulgt, hvor det er relevant, af (i) separering af de således opnåede forbindelser med formel (I) i deres respektive diastereomerer og/eller (ii) omdannelse af forbindelserne med formel (I) til deres respektive hydrater, solvater, salte og/eller hydrater eller solvater af saltene ved behandling med de tilsvarende opløsningsmidler og/eller syrer eller baser.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 4 til anvendelse til behandling og/eller forebyggelse af sygdomme.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 4 til anvendelse i en fremgangsmåde til behandling og/eller forebyggelse af akut og kronisk hjerteinsufficiens, kardiorenalt syndrom, hypervolæmisk og euvolæmisk hyponatriæmi, levercirrose, ascites, ødem og SIADH (syndrom med utilstrækkelig ADH-sekretion).
8. Anvendelse af en forbindelse ifølge et hvilket som helst af kravene 1 til 4 til fremstilling af en farmaceutisk sammensætning til behandling og/eller forebyggelse af akut og kronisk hjerteinsufficiens, kardiorenalt syndrom, hypervolæmisk og euvolæmisk hyponatriæmi, levercirrose,
ascites, ødem og SIADH (syndrom med utilstrækkelig ADH-sekretion).
9. Farmaceutisk sammensætning, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1 til 4 og et eller flere farmaceutisk acceptable excipienser.
10. Farmaceutisk sammensætning ifølge krav 9, der endvidere omfatter et eller flere yderligere terapeutiske midler valgt fra gruppen, der består af diuretika, angiotensin-AII-antagonister, ACE-inhibitorer, beta-receptorblokkere, mineralokortikoidreceptorantagonister, organiske nitrater, NO-donorer, aktivatorer af den opløselige guanylatcyclase, stimulatorer af den opløselige guanylatcyclase og positivt inotrope midler.
11. Farmaceutisk sammensætning ifølge krav 9 eller 10 til behandling og/eller forebyggelse af akut og kronisk hjerteinsufficiens, kardiorenalt syndrom, hypervolæmisk og euvolæmisk hyponatriæmi, levercirrose, ascites, ødem og SIADH (syndrom med utilstrækkelig ADH-sekretion).
12. 5- (4-chlorphenyl)-2-({1-(3-chlorphenyl)-5-[ (IS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[ (2S)-3,3,3-trifluor-2-hydroxypropyl]-2,4-dihydro-3H, 2,4-triazol-3-on ifølge krav 1 med følgende formel
eller et farmaceutisk acceptabelt salt, hydrat og/eller solvat deraf.
13. Forbindelse ifølge krav 12, hvor forbindelsen er 5— (4 — chlorphenyl)-2-({1-(3-chlorphenyl)-5-[(IS)-1-hydroxyethyl]-1H- 1,2,4-triazol-3-yl}methyl)-4-[ (2S)-3,3,3-trifluor-2-
hydroxypropyl]-2,4-dihydro-3H-l,2,4-triazol-3-on med følgende formel
DK15788389.3T 2014-11-03 2015-10-30 Hydroxyalkylsubstituerede phenyltriazolderivater og anvendelser deraf DK3215498T3 (da)

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