SI3149002T1 - Derivati 5-oksa-2-azabiciklo(2.2.2)oktan-4-ila in 5-oksa-2-azabiciklo(2.2.1)heptan-4-ila kot modulatorji receptorja TAAR1 - Google Patents

Derivati 5-oksa-2-azabiciklo(2.2.2)oktan-4-ila in 5-oksa-2-azabiciklo(2.2.1)heptan-4-ila kot modulatorji receptorja TAAR1 Download PDF

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SI3149002T1
SI3149002T1 SI201530292T SI201530292T SI3149002T1 SI 3149002 T1 SI3149002 T1 SI 3149002T1 SI 201530292 T SI201530292 T SI 201530292T SI 201530292 T SI201530292 T SI 201530292T SI 3149002 T1 SI3149002 T1 SI 3149002T1
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phenyl
azabicyclo
oxa
heptan
disorders
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Giuseppe Cecere
Guido Galley
Yimin Hu
Roger Norcross
Philippe Pflieger
Hong Shen
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F.Hoffmann-La Roche Ag
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Claims (14)

  1. Derivati 5-oksa-2-azabiciklo[2.2.2]oktan-4-ila in 5-oksa-2-azabiciklo[2.2.1]heptan-4-ila kot modulatorji receptorja TAAR1 Patentni zahtevki
    1. Spojina s formulo
    pri čemer —C— predstavlja -CH2- ali -CH2-CH2-; X predstavlja -NH-, -C(O)NH- ali -NHC(O)NH-; Ar je fenilna oziroma 5 ali 6-členska heteroarilna skupina, ki vsebuje enega ali dva atoma N, izbrana iz skupine, ki jo tvorijo piridinil, pirimidinil, pirazolil in pirazinil; R1 predstavlja halogen, Ci.7-alkil, Ci.7-alkil, substituiran s halogenom, Ci-7-alkoksi, Ci.7-alkoksi, substituiran s C3.6-cikloalkilom, Ci_7-alkoksi, substituiran s halogenom, ali C3_6-cikloalkil; -()- predstavlja -CH2-; n predstavlja 0 ali 1; m predstavlja 0, 1 ali 2;
    ali njena farmacevtsko sprejemljiva kislinska adicijska sol, vse racemske zmesi, njihovi ustrezni enantiomeri in/ali optični izomeri.
  2. 2. Spojina s formulo I po zahtevku 1, pri čemer —C— predstavlja -CH2-, n pa predstavlja 1.
  3. 3. Spojina s formulo I po zahtevku 2, v kateri so spojine: 1 -(4-klorofeni l)-3-[4-[[( 1 S,4S)-5-oksa-2-azabiciklo[2.2.1 ]heptan-4-il]metil]fenil]sečnina, 1-(3-klorofenil)-3-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4- il]metil]fenil]sečnina, 1-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-3-[4- (trifluorometil)fenil]sečnina, 1 -(2-klorofeni l)-3-[4-[[( 1 S,4S)-5-oksa-2-azabiciklo[2.2.1 ]heptan-4-il]metil]fenil]sečnina, 1 -[4-[[(1 S,4S)-5-oksa-2-azabiciklo[2.2.1 ]heptan-4-il]metil]fenil]-3-[3-(trifluorometil)fenil]sečnina, 4-kloro-N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]benzamid, 4-kloro-N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-3-propil-1 H-pirazol-5-karboksamid, 3- kloro-N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]benzamid, N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-2- (trifluorometil)piridin-4-karboksamid, 4- etoksi-N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]benzamid, 1 -[4-[[( 1 R,4R)-5-oksa-2-azabiciklo[2.2.1 ]hepta η-4-i l]meti l]fen i l]-3-[4-(trifluorometil)fenil]sečnina, 1- (4-klorofenil)-3-[4-[[(1R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]sečnina, 1 -(3-klorofeni l)-3-[4-[[( 1 R,4R)-5-oksa-2-azabiciklo[2.2.1 ]heptan-4-il]metil]fenil]sečnina, 4-(ciklopropilmetoksi)-N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4- il]metil]fenil]benzamid, 6-etoksi-N-[4-[[(1 S,4S)-5-oksa-2-azabiciklo[2.2.1 ]hepta η-4-i l]meti l]fen il]p irid in-3-karboksamid, N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-6-(2,2,2- trifluoroetoksi)piridin-3-karboksamid, 2- ciklopropil-N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4- il]metil]fenil]pirimidin-5-karboksamid, 4- kloro-3-ciklopropil-N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-1H-pirazol-5-karboksamid, 5- kloro-N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]piridin-2-amin, N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-5- (trifluorometil)piridin-2-amin, N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-5- (trifluorometil)pirazin-2-amin, N-[4-[[(1S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-5- (trifluorometil)pirimidin-2-amin, 3-izopropil-N-[4-[[(1 S,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-1 H-pirazol-5-karboksamid, 3- kloro-N-[4-[[(1R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]benzamid, N-[4-[[(1R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-2- (trifluorometil)piridin-4-karboksamid, 4- kloro-N-[4-[[(1R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-3-propil-1 H-pirazol-5-karboksamid, 5- kloro-N-[4-[[(1R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]piridin-2-amin, 1-(2-klorofenil)-3-[4-[[(1R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4- il]metil]fenil]sečnina, 1 -[4-[[( 1 R,4R)-5-oksa-2-azabiciklo[2.2.1 ]hepta η-4-il] metil]fen i l]-3-[3-(trifluorometil)fenil]sečnina, 4-(ciklopropilmetoksi)-N-[4-[[(1R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4- il]metil]fenil]benzamid, 6- etoksi-N-[4-[[(1 R,4R)-5-oksa-2-azabiciklo[2.2.1 ] heptan-4-il]metil]fen iljpirid in-3-karboksamid, N-[4-[[(1R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-6-(2,2,2- trifluoroetoksi)piridin-3-karboksamid, 4-kloro-3-ciklopropil-N-[4-[[(1R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4- il]metil]fenil]-1H-pirazol-5-karboksamid, 4-etoksi-N-[4-[[(1 R,4R)-5-oksa-2-azabiciklo[2.2.1 ]heptan-4- il]metil]fenil]benzamid, 2-etil-N-[4-[[(1 R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]pirimidin-5-karboksamid, 2- ciklopropil-N-[4-[[(1R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]pirimidin-5-karboksamid, 3- izopropil-N-[4-[[(1R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-1H-pirazol-5-karboksamid ali N-[4-[[(1R,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]metil]fenil]-5- (trifluorometil)piridin-2-amin.
  4. 4. Spojina s formulo I po zahtevku 1, pri čemer —C— predstavlja -CH2-, n pa predstavlja 0.
  5. 5. Spojina s formulo I po zahtevku 4, v kateri so spojine: 5-kloro-N-[4-[(1S,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]fenil]piridin-2-amin, 5-kloro-N-[4-[(1R,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]fenil]piridin-2-amin, 4- kloro-N-[4-[(1R,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]fenil]benzamid, 3- kloro-N-[4-[(1R,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]fenil]benzamid, N-[4-[(1R,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]fenil]-2- (trifluorometil)pirimidin-4-amin, N-[4-[(1R,4S)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]fenil]-2-(trifluorometil)piridin- 4- amin, 4-kloro-N-[4-[(1S,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]fenil]benzamid, 3- kloro-N-[4-[(1S,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]fenil]benzamid, N-[4-[(1S,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]fenil]-2-(trifluorometil)piridin- 4- karboksamid, N-[4-[(1S,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]fenil]-5-(trifluorometil)piridin- 2- amin ali N-[4-[(1S,4R)-5-oksa-2-azabiciklo[2.2.1]heptan-4-il]fenil]-2- (trifluorometil)pirimidin-4-amin.
  6. 6. Spojina s formulo I po zahtevku 1, pri čemer —C— predstavlja -CH2CH2, n pa predstavlja 1.
  7. 7. Spojina s formulo I po zahtevku 1, pri čemer —C— predstavlja -CH2CH2, n pa predstavlja 0.
  8. 8. Spojina s formulo I po zahtevku 7, v kateri so spojine: (RS)-5-kloro-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]piridin-2-amin, (RS)-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]-5-(trifluorometil)piridin-2- amin, (RS)-4-kloro-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]benzamid, 3- kloro-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]benzamid, (RS)-4-(ciklopropilmetoksi)-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4- il)fenil]benzamid, (RS)-6-etoksi-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]piridin-3- karboksamid, (RS)-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]-6-(2,2,2- trifluoroetoksi)piridin-3-karboksamid, (RS)-2-ciklopropil-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]pirimidin-5- karboksamid, (RS)-4-kloro-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]-3-propil-1 H-pirazol- 5-karboksamid, (RS)-2-etil-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]pirimidin-5- karboksamid, N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]-2-(trifluorometil)pirimidin-4-amin, (RS)-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]-2-(trifluorometil)pirimidin-4- karboksamid, 4-etoksi-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]benzamid, (RS)-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]-5-(trifluorometil)pirazin-2- amin, (RS)-N-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]-5-(trifluorometil)piridin-2- amin, (RS)-1-(4-klorofenil)-3-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]sečnina, (RS)-1-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]-3-[4-(trifluorometil)fenil]sečnina ali (RS)-1-(3-klorofenil)-3-[4-(5-oksa-2-azabiciklo[2.2.2]oktan-4-il)fenil]sečnina.
  9. 9. Postopek za pripravo spojine s formulo I po katerem koli od zahtevkov od 1 do 8, ki obsega: a) odcepitev N-zaščitne skupine (R2) s spojin s formulo na spojino s formulo
    pri čemer R2 predstavlja N-zaščitno skupino, ki je izbrana izmed -C(O)O-terc-butila ali BOC, ostale opredelitve pa ustrezajo opisom v zahtevku 1, in, če je želeno, se pridobljene spojine pretvorijo v farmacevtsko sprejemljive kislinske adicijske soli.
  10. 10. Farmacevtska zmes, ki vsebuje spojino s formulo po katerem koli od zahtevkov od 1 do 8 ter farmacevtsko sprejemljiv prenašalec in/ali adjuvans.
  11. 11. Farmacevtska zmes, ki jo sestavljajo spojina po katerem koli od zahtevkov od 1 do 8 ter farmacevtsko sprejemljiv prenašalec in/ali adjuvans za uporabo pri zdravljenju depresije, motenj anksioznosti, bipolarnih motenj, motenj pomanjkanja pozornosti (ADHD), s stresom povezanih motenj, psihotičnih motenj, shizofrenije, nevroloških bolezni, Parkinsonove bolezni, nevrodegenerativnih bolezni, Alzheimerjeve bolezni, epilepsije, migrene, hipertenzije, zlorabe snovi, presnovnih motenj, motenj hranjenja, sladkorne bolezni, s sladkorno boleznijo povezanih zapletov, čezmerne
    telesne mase, dislipidemije, motenj porabe in asimilacije energije, motenj in nepravilnosti v homeostazi telesne temperature, motenj spanja in cirkadianega ritma ter srčno-žilnih motenj.
  12. 12. Spojine po katerem koli od zahtevkov od 1 do 8 za uporabo kot zdravilne učinkovine.
  13. 13. Spojine po katerem koli zahtevku od 1 do 8 za uporabo kot zdravilne učinkovine pri zdravljenju depresije, motenj anksioznosti, bipolarnih motenj, motenj pomanjkanja pozornosti (ADHD), s stresom povezanih motenj, psihotičnih motenj, shizofrenije, nevroloških bolezni, Parkinsonove bolezni, nevrodegenerativnih bolezni, Alzheimerjeve bolezni, epilepsije, migrene, hipertenzije, zlorabe snovi, presnovnih motenj, motenj hranjenja, sladkorne bolezni, s sladkorno boleznijo povezanih zapletov, čezmerne telesne mase, dislipidemije, motenj porabe in asimilacije energije, motenj in nepravilnosti pri homeostazi telesne temperature, motenj spanja in cirkadianega ritma ter srčno-žilnih motenj.
  14. 14. Uporaba spojine po katerem koli zahtevku od 1 do 8 za pripravo zdravil za kurativno in/ali profilaktično zdravljenje depresije, motenj anksioznosti, bipolarnih motenj, motenj pomanjkanja pozornosti (ADHD), s stresom povezanih motenj, psihotičnih motenj, shizofrenije, nevroloških bolezni, Parkinsonove bolezni, nevrodegenerativnih bolezni, Alzheimerjeve bolezni, epilepsije, migrene, hipertenzije, zlorabe snovi, presnovnih motenj, motenj hranjenja, sladkorne bolezni, s sladkorno boleznijo povezanih zapletov, čezmerne telesne mase, dislipidemije, motenj porabe in asimilacije energije, motenj in nepravilnosti v homeostazi telesne temperature, motenj spanja in cirkadianega ritma ter srčno-žilnih motenj.
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