DK2729445T3 - Cykliske aminderivater som ep4-receptorantagonister - Google Patents

Cykliske aminderivater som ep4-receptorantagonister Download PDF

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DK2729445T3
DK2729445T3 DK11743035.5T DK11743035T DK2729445T3 DK 2729445 T3 DK2729445 T3 DK 2729445T3 DK 11743035 T DK11743035 T DK 11743035T DK 2729445 T3 DK2729445 T3 DK 2729445T3
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trifluoromethyl
carboxamido
benzyl
cyclopropyl
methyl
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Manuela Borriello
Sabrina Pucci
Luigi Piero Stasi
Lucio Rovati
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Rottapharm Biotech Srl
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Claims (29)

1. Cyklisk aminforbindelse med formel (I):
eller et farmaceutisk acceptabelt salt deraf, hvor: A er udvalgt fra gruppen bestående af
hvor n= 0, 1 eller 2 m= 0 eller 1 Ri og R2 uafhængigt er hydrogen, lineært eller forgrenet C-i-3 alkyl eller er forbundet med hinanden for at danne en cyclopropylring, R3 er H eller lineært eller forgrenet C-i-3 alkyl R4 og R5 uafhængigt er hydrogen, fluorin, lineært eller forgrenet C1-3 alkyl eller er forbundet med hinanden for at danne en cyclopropylring, Ar er - phenyl med: i. i 4-position en substituent udvalgt fra gruppen bestående af halogen,cyano, trifluormethyl eller ii. i 3-position en substituent udvalgt fra gruppen bestående af halogen, cyano, trifluormethyl, forudsat at ii.a., når A er B, både R4 og R5 er fluorin, lineært eller forgrenet Ci_3 alkyl, eller de danner en cyclopropylring, når de er forbundet med hinanden, ii.b. A er C, og m er 0 ii.c. A er D,og m er 1, - en 5-leddet heteroaromatisk ring indeholdende 1 til 3 heteroatomer, hvor heteroatomerne uafhængigt af hinanden er S, O eller N; eller - en 6-leddet heteroaromatisk ring indeholdende 1 til 3 N.
2. Cyklisk aminforbindelse med formel (I) ifølge krav 1, hvor Ar er phenyl med i 4 position en substituent udvalgt fra fluorin, cyano eller trifluormethyl.
3. Cyklisk aminforbindelse med formel (I) ifølge krav 2, hvor Ri er hydrogen, og R2 er methyl, eller både Ri og R2 er tilknyttet hinanden for at danne en cyclopropylring.
4. Cyklisk aminforbindelse ifølge krav 1, hvor A er B og er af formlen IB
, og/eller farmaceutisk acceptable salte deraf, hvor n= 0, 1 eller 2 'Ri og R2 uafhængigt er hydrogen, lineært eller forgrenet C1-3 alkyl eller er forbundet med hinanden for at danne en cyclopropylring, R3 er H eller lineært eller forgrenet C1-3 alkyl, R4 og R5 uafhængigt er hydrogen, fluorin, lineært eller forgrenet C1-3 alkyl eller er forbundet med hinanden for at danne en cyclopropylring, Ar er - phenyl med: i. i 4-position en substituent udvalgt fra gruppen bestående af halogen, cyano, trifluormethyl eller ii. i 3-position en substituent udvalgt fra gruppen bestående af halogen, cyano, trifluormethyl, forudsat at både R4 og R5 er fluorin, lineært eller forgrenet C1-3 alkyl eller er forbundet med hinanden for at danne en cyclopropylring, - en 5-leddet heteroaromatisk ring indeholdende 1 til 3 heteroatomer, hvor heteroatomerne uafhængigt af hinanden er S, O eller N; eller - en 6-leddet heteroaromatisk ring indeholdende 1 til 3 N.
5. Cyklisk aminforbindelse med formel (IB) ifølge krav 4, hvor Ar er phenyl med i 4-position en udvalgt fra fluorin, cyano og trifluormethyl.
6. Cyklisk aminforbindelse med formel (IB) ifølge krav 4 eller 5, hvor Ri og R2 er methyl eller er bundet til hinanden for at danne en cyclopropylring.
7. Cyklisk aminforbindelse med formel (IB) ifølge et af kravene 4 - 6, hvor R3 er hydrogen.
8. Cyklisk aminforbindelse med formel (IB) ifølge et af kravene 4 - 7, hvor R4 og R5 uafhængigt er udvalgt fra hydrogen, fluorin, methyl eller er tilknyttet hinanden for at danne en cyclopropylring.
9. Cyklisk aminforbindelse med formel (IB) ifølge et af kravene 4 - 8, hvor n er 1, og R4 og R5 uafhængigt er udvalgt fra hydrogen, fluorin, methyl.
10. Cyklisk aminforbindelse med formel (IB) ifølge et af kravene 4 - 8, hvor n er 2, og Ar er phenyl substitueret i 4 position med en substituent udvalgt fra fluorin, cyano eller trifluormethyl.
11. Cyklisk aminforbindelse med formel (IB) ifølge et af kravene 4 - 8 eller 10, hvor n er 2, både R4 og R5 er fluorin eller er tilknyttet hinanden for at danne en cyclopropylring.
12. Cyklisk aminforbindelse ifølge krav 1, hvor A er C og er af formlen IC,
og/eller farmaceutisk acceptable salte deraf, hvor m= 0 eller 1 Ri og R2 uafhængigt er hydrogen, lineært eller forgrenet C-|.3 alkyl, eller de danner en cyclopropylring, når de er forbundet med hinanden. R3 er H eller lineært eller forgrenet (C-|.3)alkyl, Ar er - phenyl med i) i 4-position halogen, cyano eller trifluormethyl eller ii) i 3-position halogen, cyano, trifluormethyl, forudsat at m er 0, - en 5-leddet heteroaromatisk ring indeholdende 1 til 3 heteroatomer, hvor heteroatomerne uafhængigt af hinanden er S, O eller N; eller - en 6-leddet heteroaromatisk ring indeholdende 1 til 3 N.
13. Cyklisk aminforbindelse med formel (IC) ifølge krav 12, hvor Ar er phenyl med i 4-position en substituent udvalgt fra fluorin, cyano eller trifluormethyl.
14. Cyklisk aminforbindelse med formel (IC) ifølge krav 12 eller 13, hvor Ri og R2 er bundet til hinanden for at danne en cyclopropylring.
15. Cyklisk aminforbindelse med formel (IC) ifølge et af kravene 12 - 14, hvor R3 er hydrogen eller methyl.
16. Cyklisk aminforbindelse med formel (IC) ifølge et af kravene 12 - 15, hvor m er 0, og Ar er phenyl substitueret i 4 position med en substituent udvalgt fra fluorin, cyano eller trifluormethyl.
17. Cyklisk aminforbindelse ifølge krav 1, hvor A er D og er af formlen (ID),
og/eller farmaceutisk acceptable salte deraf, hvor m= 0 eller 1 Ri og R2 uafhængigt er hydrogen, lineært eller forgrenet C-i-3 alkyl eller forbundet med hinanden for at danne en cyclopropylring, R3 er H eller lineært eller forgrenet C-|.3 alkyl, Ar er - phenyl med i) i 4-position halogen, cyano eller trifluormethyl eller ii) i 3-position halogen, cyano eller trifluormethyl, forudsat at m er 1, - en 5-leddet heteroaromatisk ring indeholdende 1 til 3 heteroatomer, hvor heteroatomerne uafhængigt af hinanden er S, O eller N; eller - en 6-leddet heteroaromatisk ring indeholdende 1 til 3 N.
18. Cyklisk aminforbindelse med formel (ID) ifølge krav 17, hvor Ar er phenyl med i 4-position fluorin, cyano eller trifluormethyl.
19. Cyklisk aminforbindelse med formel (ID) ifølge krav 17 eller 18, hvor Ri og R2 er bundet til hinanden for at danne en cyclopropylring.
20. Cyklisk aminforbindelse med formel (ID) ifølge et af kravene 17 - 19, hvor R3 er hydrogen eller methyl.
21. Cyklisk aminforbindelse med formel (ID) ifølge et af kravene 17 - 19, hvor m er 1, og Ar er phenyl substitueret i 4 position med en substituent udvalgt fra gruppen bestående af fluorin, chlorin, cyano eller trifluormethyl.
22. Cyklisk aminforbindelse ifølge krav 1, hvor A er E og er af formlen (IE),
og/eller farmaceutisk acceptable salte deraf, hvor Ri og R2 uafhængigt er hydrogen, lineært eller forgrenet C-i-3 alkyl, eller de danner en cyclopropylring, når de er forbundet med hinanden, R3 er H eller lineært eller forgrenet C-i-3 alkyl, Ar er - phenyl med i 3 eller 4-position halogen, cyano eller trifluormethyl, - en 5-leddet heteroaromatisk ring indeholdende 1 til 3 heteroatomer, hvor heteroatomerne uafhængigt af hinanden er S, O eller N; eller - en 6-leddet heteroaromatisk ring indeholdende 1 til 3 N.
23. Cyklisk aminforbindelse med formel (IE) ifølge krav 22, hvor Ar er phenyl med i 4-position en substituent udvalgt fra fluorin, cyano eller trifluormethyl.
24. Cyklisk aminforbindelse med formel (IE) ifølge krav 22 eller 23, hvor R1 er hydrogen, og R2 er methyl, eller både Ri og R2 er bundet til hinanden for at danne en cyclopropylring.
25. Cyklisk aminforbindelse med formel (IE) ifølge et af kravene 22 - 24, hvor R3 er hydrogen eller methyl.
26. Forbindelse ifølge krav 1, udvalgt fra gruppen bestående af litium (R)-4-(1 -(1 -(4-(trifluormethyl)benzyl)piperidin-2- carboxamido)cyclopropyl) benzoat 4-(1-(6-(4-(trifluormethyl)benzyl)-6-azaspiro[2.5]oktan-5-carboxamido)cyclopropyl) benzoesyre carboxamido)cyclopropyl)benzoesyre 4-((1 S)-1 -(6-(4-(trifluormethyl)benzyl)-6-azaspiro[2.5]oktan-5-carboxamido)ethyl) benzoesyre 4-((1 S)-1 -(4,4-dimethyl-1 -(4-(trifluormethyl)benzyl)piperidin-2-carboxamido)ethyl) benzoesyre 4-((S)-1-((F?)-4,4-difluor-1-(4-(trifluormethyl)benzyl)piperidin-2-carboxamido)ethyl) benzoesyre (R)-4-(1 -(4,4-difluor-1 -(4-(trifluormethyl)benzyl)piperidin-2-carboxamido) cy-clopropyl)benzoesyre 4-(1 -(4,4-difluor-1 -(4-(trifluormethyl)benzyl)piperidin-2- carboxamido)cyclopropyl) benzoesyre 4-(1 -(4,4-difluor-1 -(3-(trifluormethyl)benzyl)piperidin-2- carboxamido)cyclopropyl) benzoesyre 4-(1 -(4,4-difluor-1 -(3-(trifluormethyl)benzyl)piperidin-2- carboxamido)cyclopropyl) benzoesyre 4-(1-(3-(4-(trifluormethyl)benzyl)-3-azabicyclo[4.1.0]heptan-4-carboxamido) cyclopropyl)benzoesyre 4-(1-((3F?)-2-(4-(trifluormethyl)benzyl)-2-azabicyclo[4.1,0]heptan-3-carboxamido) cyclopropyl)benzoesyre 4-((1 S)-1 -((3F?)-2-(4-(trifluormethyl)benzyl)-2-azabicyclo[4.1,0]heptan-3-carboxamido)ethyl)benzoesyre litium 4-((S)-1 -{{R}-1 -(4-(trifluormethyl)benzyl)pyrrolidin-2-carboxamido)ethyl) benzoat 4-(1 -((1 F?,3/:?,5/:?)-2-(3-(trifluormethyl)benzyl)-2-azabicyclo[3.1.0]hexan-3-carboxamido)cyclopropyl)benzoesyre 4-(1 -((1 F?,3/:?,5/:?)-2-(4-(thfluormethyl)benzyl)-2-azabicyclo[3.1.0]hexan-3- carboxamido)cyclopropyl)benzoesyre.
27. Farmaceutisk sammensætning omfattende en forbindelse med formel (I) ifølge et af kravene 1-26 eller et farmaceutisk acceptabelt salt deraf og et farmaceutisk acceptabelt bærestof og/eller hjælpestof.
28. Forbindelse med formel (I) ifølge et af kravene 1-26 til anvendelse som et medikament.
29. Forbindelse med formel (I) ifølge et af kravene 1-26 til anvendelse ved behandling af sygdomme udvalgt fra akut og kronisk smerte, inflammatorisk smerte, inflammationsassocierede sygdomme, osteoartritis og reumatoid artritis.
DK11743035.5T 2011-07-04 2011-07-04 Cykliske aminderivater som ep4-receptorantagonister DK2729445T3 (da)

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