DK2234979T3 - 5-[(3,3,3-trifluor-2-hydroxy-1-arylpropyl)amino]-1H-quinolin-2-oner, fremgangsmåde til fremstilling deraf og anvendelse deraf som antiinflammatoriske midler - Google Patents

5-[(3,3,3-trifluor-2-hydroxy-1-arylpropyl)amino]-1H-quinolin-2-oner, fremgangsmåde til fremstilling deraf og anvendelse deraf som antiinflammatoriske midler Download PDF

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DK2234979T3
DK2234979T3 DK08852223.0T DK08852223T DK2234979T3 DK 2234979 T3 DK2234979 T3 DK 2234979T3 DK 08852223 T DK08852223 T DK 08852223T DK 2234979 T3 DK2234979 T3 DK 2234979T3
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fluoro
chloro
quinolin
trifluoro
amino
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Hartmut Rehwinkel
Thomas Zollner
Ekkehard May
Jorma Hassfeld
Heike Schäcke
Markus Berger
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Bayer Ip Gmbh
Astrazeneca Ab
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 (25)

1. Forbindelser med den almene formel I RSΩΗ
) hvor R1 og R2 uafhængigt af hinanden er hydrogen, fluor, chlor eller en methoxygruppe; R3 er hydrogen, fluor, chlor eller en methoxygruppe; R4 er fluor; R5 er en hydroxygruppe, et chloratom, -S-CH3, -S-CH2-CH3, -0-CH3 eller -0-CH2-CH3; og deres salte, solvater eller salte af solvater.
2. Forbindelser med den almene formel I ifølge krav 1, hvilke forbindelser er valgt fra listen bestående af 5-{[1-(2-chlor-3-fluor-4-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2-([methylsulfanyl]methyl) propyl]amino}-7-fluor-1H-quinolin-2-on 5-{[1-(2-chlor-3-fluor-4-methoxyphenyl)-2- ([ethylsulfanyl]methyl)-3,3,3-trifluor-2-hydroxypropyl]amino}-7-fluor-lH-quinolin-2-on 5-{[1-(2-chlor-3-fluor-4-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluor-lH-quinolin-2-on 5-{[1-(2-chlor-3-fluor-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluor-2-hydroxypropy1]amino}-7-fluor-lH-quinolin-2-on 5-{[1-(2-chlor-3-fluor-4-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2-(hydroxymethyl) propyl]amino}-7-fluor-lH-quinolin-2-on 5-{[1-(5-chlor-3-fluor-2-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2-(hydroxymethyl)-propyl]amino}-7-fluor-lH-quinolin-2- on 5-{[1-(5-chlor-3-fluor-2-methoxyphenyl)-2-(chlormethyl)-3,3,3-trifluor-2-hydroxypropyl]amino}-7-fluor-lH-quinolin-2-on 5-{[1-(4-chlor-3-fluor-2-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluor-lH-quinolin-2-on 5-{[1-(4-chlor-3-fluor-2-methoxyphenyl)-2-(ethoxymethyl) -3,3,3-trifluor-2-hydroxypropyl]amino}-7-fluor-lH-quinolin-2-on 5-{[1-(2-chlor-3-fluor-4-hydroxyphenyl)-3,3,3-trifluor-2-hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluor-lH-quinolin-2-on og deres salte, solvater eller salte af solvater.
3. Enantiomert rene forbindelser ifølge krav 1, hvilke forbindelser er valgt fra listen bestående af 5-{(IS,2R)[1-(2-chlor-3-fluor-4-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2-([methylsulfanyl]methyl) propyl]amino}-7-fluor-ΙΗ-quinolin-2-on 5-{(1S,2R)[1-(2-chlor-3-fluor-4-methoxyphenyl)-2-([ethylsulfanyl]methyl)-3,3,3-trifluor-2-hydroxypropyl]amino}-7-fluor-lH-quinolin-2-on 5-{(IS,2S)[1-(2-chlor-3-fluor-4-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2-(methoxymethyl) propyl]amino}-7-fluor-ΙΗ-quinolin-2-on 5-{(1S,2S)[1-(2-chlor-3-fluor-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluor-2-hydroxypropyl]amino}-7-fluor-lH-quinolin-2-on 5-{ (IS,2 S) [1-(2-chlor-3-fluor-4-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2-(hydroxymethyl) propyl]amino}-7-fluor-lH-quinolin-2-on 5-{(IS,2S)[1-(5-chlor-3-fluor-2-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2-(hydroxymethyl) propyl]amino}-7-fluor-lH-quinolin-2-on 5-{(1S,2R)[1-(5-chlor-3-fluor-2-methoxyphenyl)-2-(chlormethyl)-3,3,3-trifluor-2-hydroxypropyl]amino}-7-fluor-lH-quinolin-2-on 5-{ [ (IS,2S) [1-(2-chlor-3-fluor-4-hydroxyphenyl)-3,3,3- trifluor-2-hydroxy-2-(hydroxymethyl) propyl]amino}-7-fluor-lH- quinolin-2-on og deres salte, solvater eller salte af solvater.
4. Anvendelse af forbindelserne med formlen I ifølge mindst ét af kravene 1-3 til fremstilling af farmaceutiske midler.
5. Anvendelse af forbindelserne med formlen I ifølge mindst ét af kravene 1-3 til fremstilling af farmaceutiske midler til behandling af sygdomme valgt blandt: (i) lungesygdomme, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (ii) reumatiske sygdomme eller autoimmune sygdomme eller ledsygdomme, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (iii) allergier eller pseudoallergiske sygdomme, som er sammenfaldende med inflammatoriske og/eller proliferative processer, (iv) vaskulære inflammationer (vaskulitter) , (v) dermatologiske sygdomme, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (vi) nyresygdomme, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (vii) leversygdomme, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (viii) gastrointestinale sygdomme, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (ix) proktologiske sygdomme, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (x) øjensygdomme, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (xi) sygdomme i øre-næse-hals-området, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (xii) neurologiske sygdomme, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (xiii) blodsygdomme, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (xiv) tumorsygdomme, som er sammenfaldende med inflammatoriske og/eller proliferative processer, (xv) endokrine sygdomme, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (xvi) organ- og vævstransplantater, graft-versus-host-sygdom, (xvii) alvorlige shocktilstande, (xviii) substitutionsbehandling ved medfødt primær suprarenal insufficiens, erhvervet primær suprarenal insufficiens, medfødt sekundær suprarenal insufficiens, erhvervet sekundær suprarenal insufficiens, (xix) emesis, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer, (xx) smerter af inflammatorisk oprindelse, (xxi) forskellige andre sygdomsstadier valgt blandt type I- diabetes (insulinafhængig diabetes), osteoarthritis, Guillain-Barrés syndrom, restenoser efter perkutan transluminal angioplastik, Alzheimers sygdom, akutte og kroniske smerter, arteriosklerose, reperfusionsskade, kongestivt hjertesvigt, myokardieinfarkt, varmeskade, multiorganskade sekundært til traume, akut purulent meningitis, nekrotiserende enterocolitis og syndromer forbundet med hæmodialyse, leukoferese og granulocyttransfusion.
6. Farmaceutisk sammensætning, som omfatter en forbindelse med formlen (I) eller et farmaceutisk acceptabelt salt deraf ifølge krav 1-3 og en farmaceutisk acceptabel adjuvans, et farmaceutisk acceptabelt fortyndingsmiddel eller en farmaceutisk acceptabel bærer.
7. Fremgangsmåde til fremstilling af forbindelserne med den almene formel I ifølge krav 1, hvor der udføres følgende trin: trin al·
trin b):
(VI) . (I) hvor alle rester har definitionerne ifølge krav 1, og R er (Ci-C4)-alkyl, og Met betegner alkalimetaller, jordalkalimetaller, aluminium, kobber, silicium eller tin.
8. Fremgangsmådetrin a) ifølge krav 7 til fremstilling af mellemprodukter med den almene formel IV, kendetegnet ved, at benzaldehyder med den almene formel II omsættes med substituerede quinolonaminer med formlen III til iminer med 3 den almene formel IV i nærværelse af Lewis-syrer og/eller under sure betingelser, MU V1/
vvl hvor R1, R2, R3 og R4 har de betydninger, som er defineret i krav 1, og R er (C1-C4)-alkyl.
9. Fremgangsmådetrin b) ifølge krav 7 til fremstilling af mellemprodukter med den almene formel VI, kendetegnet ved, at metalleret trifluorepoxypropan V, eventuelt i sin enantiomert rene form, omsættes med iminer med formlen IV ved lave J J° ' 1 1 " ne formel VI hvor R1, Rz, RJ og R*1
har de betydninger, som er defineret i 5 krav 1, og at der eventuelt efterfølgende udføres en separation af diastereoisomerer.
10. Fremgangsmådetrin c) ifølge krav 7 til fremstilling af forbindelser med den almene formel I, kendetegnet ved, at 3 epoxider med den almene formel VI, eventuelt i deres enantiomert rene form, omsættes med forbindelser med den almene formel R5-Met, hvorved Met betegner alkalimetaller, jordalkalimetaller, aluminium, kobber, silicium eller tin, og R5 har definitionerne 5 ifølge krav 1, i nærværelse af Lewis-syrer eller åbnes direkte ved hjælp af cyanider, aminer, alkoholer, thioalkoholer, halogenider og/eller vand i nærværelse af baser eller stærke protiske syrer, for at opnå forbindelser med den almene formel I D5
k 3 hvor R1, R2, R3, R4 og R5 har de betydninger, som er defineret i krav 1, og at der eventuelt efterfølgende udføres en separation af diastereoisomerer.
11. Forbindelser med den almene formel VI ifølge krav 9,
(VI) i form af en racemisk blanding eller som enantiomert ren isomer.
12. Fremgangsmåde til fremstilling af forbindelserne med den almene formel I ifølge krav 1, hvor der udføres følgende trin: trin al·
(IX) o hvor alle rester har de betydninger, som er defineret i krav 1, Met betegner alkalimetaller, jordalkalimetaller, aluminium, kobber, silicium eller tin, og R er (C1-C4)-alkyl.
13. Fremgangsmådetrin c) ifølge krav 12 til fremstilling af forbindelser med den almene formel I, kendetegnet ved, at 5 ketoner af typen (IX), eventuelt i deres enantiomert rene form, kan kondenseres med substituerede aminoquinoloner af typen (III) til iminer og efterfølgende eller samtidigt reduceres for at opnå forbindelser med formlen I
Λ (I) 3 hvor R1, R2, R3, R4 og R5 har de betydninger, som er angivet i krav 1, og R er som defineret i krav 8, og at der eventuelt efterfølgende kan udføres en separation af diastereoisomerer.
14. Sammensætning, som omfatter en kombination af en 5 forbindelse med formlen (I), eller et farmaceutisk acceptabelt salt deraf, og et eller flere midler valgt fra listen omfattende: • en PDE4-hæmmer, som indbefatter en hæmmer af isoformen PDE4D; 3 · en selektiv β.sub2.-adrenoceptoragonist, såsom metaproterenol, isoproterenol, isoprenalin, albuterol, salbutamol, formoterol, salmeterol, terbutalin, orciprenalin, bitolterolmesylat, pirbuterol eller indacaterol; • en muscarinreceptorantagonist (for eksempel en Ml-, M2-5 eller M3-antagonist, såsom en selektiv M3-antagonist), såsom ipratropiumbromid, tiotropiumbromid, oxitropiumbromid, pirenzepin eller telenzepin; • en modulator af kemokinreceptorfunktion (såsom en CCR1-receptorantagonist) eller 3 »en hæmmer af p38 kinase-funktion.
15. Anvendelse ifølge krav 5, hvor sygdommen er en dermatologisk sygdom, som er sammenfaldende med inflammatoriske, allergiske og/eller proliferative processer.
16. Anvendelse ifølge krav 15, hvor den dermatologiske sygdom er valgt blandt atopisk dermatitis, alle former for eksem, udslæt af en hvilken som helst oprindelse eller dermatoser, psoriasis- og parapsoriasisgrupper, pityriasis rubra pilaris, bulløse dermatoser, sygdomme fra lichenoidgruppen, pruritis, seboroisk eksem, rosaceagruppen, erythema exudativum multiforme, balanitis, vulvitis, manifestation af vaskulære sygdomme, hårtab og kutant lymfom.
17. Anvendelse ifølge krav 15, hvor den dermatologiske sygdom er atopisk dermatitis.
18. Anvendelse ifølge krav 15, hvor den dermatologiske sygdom er psoriasis.
19. Forbindelse ifølge krav 1, som er 5-{[1-(2-chlor-3-fluor-4-methoxyphenyl)-2-([ethylsulfanyl]methyl)-3,3,3-trifluor-2-hydroxypropyl]amino}-7-fluor-lH-quinolin-2-on.
20. Forbindelse ifølge krav 1, som er 5-{ [ 1-(2-chlor-3-fluor-4-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2-(methoxymethyl) propyl]amino}-7-fluor-lH-quinolin-2-on.
21. Forbindelse ifølge krav 1, som er 5-{[1-(2-chlor-3-fluor-4-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2-(hydroxymethyl)-propyl]amino}-7-fluor-lH-quinolin-2-on.
22. Forbindelse ifølge krav 1, som er 5-{[1-(5-chlor-3-fluor-2-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2-(hydroxymethyl)-propyl]amino}-7-fluor-lH-quinolin-2-on.
23. Forbindelse ifølge krav 1, som er 5-{[1-(2-chlor-3-fluor-4-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2- ([methylsulfanyl]methyl) propyl]amino}-7-fluor-lH-quinolin-2- on .
24. Forbindelse ifølge krav 1, som er 5-{ [ 1-(2-chlor-3-fluor-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluor-2- 5 hydroxypropyl]amino}-7-fluor-lH-quinolin-2-on.
25. Forbindelse ifølge krav 1, som er 5-{ [ 1-(5-chlor-3-fluor-2-methoxyphenyl)-2-(chlormethyl)-3,3,3-trifluor-2-hydroxypropyl]amino}-7-fluor-lH-quinolin-2-on.
DK08852223.0T 2007-11-22 2008-11-08 5-[(3,3,3-trifluor-2-hydroxy-1-arylpropyl)amino]-1H-quinolin-2-oner, fremgangsmåde til fremstilling deraf og anvendelse deraf som antiinflammatoriske midler DK2234979T3 (da)

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