DK3212622T3 - Benzylhydroxidderivater, fremstilling deraf og terapeutisk anvendelse deraf - Google Patents

Benzylhydroxidderivater, fremstilling deraf og terapeutisk anvendelse deraf Download PDF

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DK3212622T3
DK3212622T3 DK15788381.0T DK15788381T DK3212622T3 DK 3212622 T3 DK3212622 T3 DK 3212622T3 DK 15788381 T DK15788381 T DK 15788381T DK 3212622 T3 DK3212622 T3 DK 3212622T3
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dimethoxyphenyl
phenyl
phenoxy
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ethanol
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Jérôme Meneyrol
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Sanofi Sa
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • A61K31/4164—1,3-Diazoles
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    • A61K31/42—Oxazoles
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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Claims (20)

1. Forbindelser med formel (I)
hvor A er en 5-leddet heteroarylgruppe, der omfatter mellem 1 og 3 heteroatomer, hvor mindst ét heteroatom er valgt blandt et svovlatom og et nitrogenatom, idet A er usubstitueret eller substitueret med en eller flere (C1-C4)alkylgrupper, og hver (C1-C4)alkylgruppe er usubstitueret eller substitueret med en heterocyclylgruppe, hver af RI, R2, RI' og R2' uafhængigt er et hydrogenatom eller en (C1-C4)alkylgruppe, og hver af R3, R4, R5, R3', R4' og R5' er valgt uafhængigt blandt et hydrogenatom, et halogenatom, en -O-fluormethylgruppe og en (C1-C4)alkoxygruppe, hvor mindst én af R3, R4 og R5 er en (Cl-C4) alkoxygruppe, og mindst én af R3' , R4 ' og R5' er en (Cl-C4)alkoxygruppe, i form af en base, enantiomerer, diastereoisomerer, herunder en racemisk blanding, og additionssalt med en syre.
2. Forbindelser med formel (I) ifølge krav 1, der er kendetegnet ved, at A er en oxazolyl-, thiazol-, thienyl-, oxadiazolyl-, thiadiazolyl- eller imidazolylgruppe, i form af en base, enantiomerer, diastereoisomerer, herunder en racemisk blanding, og additionssalt med en syre.
3. Forbindelser med formel (I) ifølge et hvilket som helst af kravene 1 og 2, der er kendetegnet ved, at A er usubstitueret, i form af en base, enantiomerer, diastereoisomerer, herunder en racemisk blanding, og additionssalt med en syre.
4. Forbindelser med formel (I) ifølge et hvilket som helst af kravene 1 og 2, der er kendetegnet ved, at A er substitueret med en eller flere methylgrupper, i form af en base, enantiomerer, diastereoisomerer, herunder en racemisk blanding, og additionssalt med en syre.
5. Forbindelser med formel (I) ifølge et hvilket som helst af kravene 1 til 4, der er kendetegnet ved, at hver af RI, R2, RI' og R2' er et hydrogenatom eller en methylgruppe, i form af en base, enantiomerer, diastereoisomerer, herunder en racemisk blanding, og additionssalt med en syre.
6. Forbindelser med formel (I) ifølge krav 5, der er kendetegnet ved, at hver af RI, R2, RI' og R2' er et hydrogenatom, i form af en base, enantiomerer, diastereoisomerer, herunder en racemisk blanding, og additionssalt med en syre.
7. Forbindelser med formel (I) ifølge et hvilket som helst af kravene 1 til 6, der er kendetegnet ved, at mindst to af R3, R4 og R5 er -OCH3, og mindst to af R3' , R4 ' og R5' er -OCH3, i form af en base, enantiomerer, diastereoisomerer, herunder en racemisk blanding, og additionssalt med en syre.
8. Forbindelser med formel (I) ifølge krav 7, der er kendetegnet ved, at to af R3, R4 og R5 er -OCH3, og to af R3' , R4' og R5' er -OCH3, i form af en base, enantiomerer, diastereoisomerer, herunder en racemisk blanding, og additionssalt med en syre.
9. Forbindelser med formel (I) ifølge et hvilket som helst af kravene 1 til 8, der er kendetegnet ved, at mindst én af R3, R4, R5, R3' , R4 ' og R5' er -OCHF2, i form af en base, enantiomerer, diastereoisomerer, herunder en racemisk blanding, og additionssalt med en syre.
10. Forbindelser med formel (I) ifølge et hvilket som helst af kravene 1 til 9, der er kendetegnet ved, at R1=R1', R2=R2', R3=R3', R4=R4' og R5=R5', i form af en base, enantiomerer, diastereoisomerer, herunder en racemisk blanding, og additionssalt med en syre.
11. Forbindelser med formel (I) ifølge krav 1, som er valgt fra følgende liste: 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]-5-methyloxazol-4-yl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1,1-dimethylethoxy]phenyl]-5-methyloxazol-4-yl]phenoxy]-2-methylpropan-l-ol ; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]-4-methyloxazol-5-yl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1,1-dimethylethoxy]phenyl]-5-methylthiazol-4-yl]phenoxy]-2-methylpropan-l-ol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]-5-methylthiazol-4-yl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1,1-dimethylethoxy]phenyl]-5-methylthiazol-4-yl]phenoxy]-2-methylpropan-l-ol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]-5-methylthiazol-4-yl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-l-methylethoxy]phenyl]oxazol-4-yl]phenoxy]propan-l-ol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]oxazol-4-yl]phenoxy]ethanol; 1-(4-chlor-3-methoxyphenyl)-2-[4-[2-[4-[2-(4-chlor-3- methoxyphenyl)-2-hydroxyethoxy]phenyl]oxazol-4- yl]phenoxy]ethanol; 1-(4-fluor-3-methoxyphenyl)-2-[4-[2-[4-[2-(4-fluor-3- methoxyphenyl)-2-hydroxyethoxy]phenyl]oxazol-4- yl]phenoxy]ethanol; 1-(3-fluor-4-methoxyphenyl)-2-[4-[2-[4-[2-(3-fluor-4- methoxyphenyl)-2-hydroxyethoxy]phenyl]oxazol-4- yl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2- hydroxy-1,1-dimethylethoxy]phenyl]oxazol-4-yl]phenoxy]-2-methylpropan-l-ol; 2-[4-[2-[4-[2-hydroxy-2- (3,4,5- trimethoxyphenyl) ethoxy]phenyl]oxazol-4-yl]phenoxy]-1-(3,4,5-trimethoxyphenyl) ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]thiazol-4-yl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1,1-dimethylethoxy]phenyl]thiazol-4-yl]phenoxy]-2-methylpropan-l-ol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-l-methylethoxy]phenyl]thiazol-4-yl]phenoxy]propan-Ιοί ; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]thiazol-4-yl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[4-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]thiazol-2-yl]phenoxy]-2-methylpropan-Ιοί ; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]thiazol-4-yl]phenoxy]-2-methylpropan-Ιοί ; 1-(3,4-dimethoxyphenyl)-2-[4-[5-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1,1-dimethylethoxy]phenyl]-3-thienyl]phenoxy]-2-methylpropan-l-ol; 1-(3,4-dimethoxyphenyl)-2-[4-[5-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]-3-thienyl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[5-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]-1,2,4-oxadiazol-3-yl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[5-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1,1-dimethylethoxy]phenyl]-1,2,4-oxadiazol-3-yl]phenoxy]-2-methylpropan-l-ol; 1-(3,4-dimethoxyphenyl)-2-[4-[5-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-l-methylethoxy]phenyl]-1,2,4-thiadiazol-3-yl]phenoxy]propan-l-ol; 1-(3,4-dimethoxyphenyl)-2-[4-[5-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]-1,2,4-thiadiazol-3-yl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[5-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1,1-dimethylethoxy]phenyl]-1,2,4-thiadiazol-3- yl]phenoxy]-2-methylpropan-l-ol ; 1-(3,4-dimethoxyphenyl)-2-[4-[5-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1,1-dimethylethoxy]phenyl]-1,2,4-thiadiazol-3-yl]phenoxy]-2-methylpropan-l-ol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1-methylethoxy]phenyl]oxazol-5-yl]phenoxy]propan-l-ol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]-lH-imidazol-4-yl]phenoxy]ethanol; 1- (3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1,1-dimethylethoxy]phenyl]-lH-imidazol-4-yl]phenoxy]- 2- methylpropan-l-ol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1,1-dimethylethoxy]phenyl]-l-methylimidazol-4-yl]phenoxy]-2-methylpropan-l-ol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]-1-methylimidazol-4-yl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1, 1-dimethylethoxy]phenyl]-1-(2- morpholinoethyl)imidazol-4-yl]phenoxy]-2-methylpropan-l-ol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]-1-(2-morpholinoethyl)imidazol-4-yl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[2-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]-4-methyloxazol-5-yl]phenoxy]ethanol; 1-(3,4-dimethoxyphenyl)-2-[4-[5-[4-[2-(3,4-dimethoxyphenyl)-2-hydroxyethoxy]phenyl]-1,2,4-oxadiazol-3-yl]phenoxy]ethanol; 1-[3-(difluormethoxy)-4-methoxyphenyl]-2-[4-[2-[4- [2- [3-(difluormethoxy)-4-methoxyphenyl]-2- hydroxyethoxy]phenyl]thiazol-4-yl]phenoxy]ethanol; og 1-[4-(difluormethoxy)-3-methoxyphenyl]-2-[4-[2-[4- [2- [4-(difluormethoxy)-3-methoxyphenyl]-2-hydroxyethoxy]phenyl]thiazol-4-yl]phenoxy]ethanol, i form af en base, enantiomerer, diastereoisomerer, herunder en racemisk blanding, og additionssalt med en syre.
12. Fremgangsmåde til fremstilling af en forbindelse med formel (I) ifølge et hvilket som helst af kravene 1 til 11, der er kendetegnet ved, at en forbindelse med formel (II)
udsættes for et reduktionstrin.
13. Fremgangsmåde til fremstilling af en forbindelse med formel (I) ifølge et hvilket som helst af kravene 1 til 11, der er kendetegnet ved, at en forbindelse med formel (III) :
udsættes for et reduktionstrin.
14. Forbindelser med formel (II)
hvor RI, R2, R3, R4, R5, RI', R2 ' , R3' , R4 ' og R5' har den samme betydning som i krav 1.
15. Forbindelser med formel (III)
hvor RI, R2, R3, R4, R5, RI', R2 ' , R3' , R4 ' og R5' har den samme betydning som i krav 1.
16. Medikament, der er kendetegnet ved, at det omfatter en forbindelse med formel (I) ifølge et hvilket som helst af kravene 1 til 11 eller et additionssalt af denne forbindelse med en farmaceutisk acceptabel syre.
17. Farmaceutisk sammensætning, der er kendetegnet ved, at den omfatter en forbindelse med formel (I) ifølge et hvilket som helst af kravene 1 til 11 eller et farmaceutisk acceptabelt salt af denne forbindelse og endvidere mindst ét farmaceutisk acceptabelt excipiens.
18. Forbindelse med formel (I) ifølge et hvilket som helst af kravene 1 til 11 til anvendelse som en inhibitor af kompleks 1 i mitokondrie-respirationskæden.
19. Forbindelse med formel (I) ifølge et hvilket som helst af kravene 1 til 11 til anvendelse til behandling af cancer.
20. Forbindelse til anvendelse ifølge krav 19, hvor canceren er valgt blandt karcinomer, der har en metabolisme, der er afhængig af oxidativ phosphorylering, såsom lungetumorer og mere specifikt ikke-småcellede lungecancere, hormonafhængige brysttumorer, ovarietumorer, hepatokarcinomer, gastroinstestinale tumorer samt pankreas- og colontumorer, overudtrykkende c-myc-tumorer, såsom lymfomer, bryst- eller coloncancer, vel- til middeldifferentierede tumorer, cancere, der inducerer primære lymfeknude-og lungemetastaser, tidlige stadier af cancere, der er beskrevet at fremvise hypoksiske
områder under deres udvikling og metabolisk adaptation (glykolytisk skift), såsom melanomer, gliomer, hoved- og halskarcinomer og leukæmier.
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