DK2176252T3 - 2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl-derivater som alpha2c-antagonister til anvendelse i behandlingen af sygdomme i det perifere nervesystem og centralnervesystemet - Google Patents

2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl-derivater som alpha2c-antagonister til anvendelse i behandlingen af sygdomme i det perifere nervesystem og centralnervesystemet Download PDF

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DK2176252T3
DK2176252T3 DK08787689.2T DK08787689T DK2176252T3 DK 2176252 T3 DK2176252 T3 DK 2176252T3 DK 08787689 T DK08787689 T DK 08787689T DK 2176252 T3 DK2176252 T3 DK 2176252T3
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dioxin
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Belle David Din
Patrik Holm
Arto Karljalainen
Arto Tolvanen
Gerd Wohlfahrt
Petteri Rummakko
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Claims (25)

1. Forbindelse ifølge formel I,
I hvor X er C(R5)(R6) eller C(R7)(R8); Z er -[C(R4)2]n- eller en enkeltbinding; Ri er, ved hver forekomst, uafhængigt hydroxy, (Ci-Ce)alkyl, (Cr C6)alkoxy, halogen, halo(Ci-C6)alkyl, fenyl(Ci-C6)alkoxy, (Ci-Ce)alkoxy-(C=0)-, CN, NO2, NH2, mono- eller di(Ci-C6)alkylamino eller carboxy; R2 er, ved hver forekomst, uafhængigt H eller (Ci-Ce)alkyl; R3 er, ved hver forekomst, uafhængigt H eller (Ci-Ce)alkyl; R4 er, ved hver forekomst, uafhængigt H, hydroxy, (Ci-Ce)alkyl, (C2-C6)alkenyl, hydroxy(Ci-Ce)alkyl, hydroxy(C2-Ce)alkenyl, (C1-C6)al koxy(Ci-C6)al kyl, (C2-Ce)alkenyloxy(Ci-Ce)alkyl, (C1 -Ce)al kyl-(C=0)-, (CrC6)alkoxy-(C=0)-, hydroxy(Ci-C6)alkoxy(Ci-C6)alkyl eller (C1-C6)alkoxy(Ci-C6)alkoxy(Ci-C6)alkyl; eller R4 og R4, begge bundet til det samme kulstofringatom, danner sammen med det kulstofringatom, de er bundet til, en -(C=0)- gruppe; R5 er H eller hydroxy; eller R4 og R5, bundet til naboliggende kulstofringatomer, danner en binding mellem de kulstofringatomer, de er bundet til; R6 er fenyl, der er usubstitueret eller substitueret med 1 eller 2 substituent(er) R9; R7 er (Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy(CrC6)alkyl eller (Ci-C6)alkoxy-(C=0)-; R8 er hydroxy, (Ci-C6)alkyl, (C2-C6)alkenyl, (Ci-C6)alkoxy, halogen, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(C2-C8)alkenyl, hydroxy(Ci-C6)alkoxy, halo(Ci-C6)alkoxy, fenyl(Ci-C6)alkoxy, (Cr C6)al koxy(Ci-C6)al kyl, (C2-C8)alkenyloxy(Ci-C8)alkyl, (Ci -C8)al kyl-(C=0)-, (Ci-C6)alkoxy-(C=0)-, (Ci-C6)alkoxy-(C=0)-(Ci-C6)alkyl, (Cr C6)alkyl-S-, (Ci-C6)alkyl-(C=0)-0-, (Ci-C6)alkyl-(C=0)-0-(Ci-C6)alkyl, hydroxy-(C=0)-(Ci-C6)alkoxy, hydroxy-(C=0)-(Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxy-(C=0)-(Ci-C6)alkoxy(CrC6)alkyl, (Ci-C6)alkyl-S-(Cr C6)alkyl, hydroxy(Ci-C6)alkyl-S-(Ci-C6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl-S-(Ci-Ce)alkyl, (Ci-C6)alkyl-(C=0)-S-(Ci-C6)alkyl, (Ci-C6)alkoxy-(C=0)-(Ci-C6)alkyl-S-(CrC6)alkyl, (Ci-C6)alkyl-S-(Ci-C6)alkoxy(CrC6)alkyl, hydroxy(Ci-C6)alkyl-S-(Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl-S-(Ci-C6)alkoxy(Ci-C6)al kyl, (Ci-C6)alkyl-(0=S=0)-(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl-(0=S=0)-(Ci-C6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl-(0=S=0)-(Ci-C6)alkyl, (Ci-C6)alkyl-(0=S=OHCi-C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl-(0=S=0)-(Ci-C6)alkoxy(Ci-C6)alkyl, (Cr C6)al koxy(Ci-C6)alkyl-(0=S=0)-(Ci-C8)alkoxy(Ci-C8)alkyl, (Ci -C8)alkyl- 0-(0=S=0)-(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl-0-(0=S=0)-(Ci-C6)alkyl, (Ci-C6)alkyl-(0=S=0)-0-(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl-(0=S=0)-0-(Ci-C6)alkyl, (Ci-C6)alkyl-(0=S=0)-N(Ri0)-(Ci-C6)alkyl, hydroxy(Cr C6)alkoxy(CrC6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkoxy(CrC6)alkyl, halo(Cr C6)alkoxy(Ci-C6)alkyl, CN, N02, (Rio)2N-, (Ri0)2N-(Ci-C6)alkyI, (Rio)2N-(C=0)-, (Rio)2N-(C=OHCi-C6)alkoxy(Ci-C6)alkyl, (Rio)2N-(C=0)-(Ci-C6)alkyl-S-(Ci-C6)alkyl, (Rio)2N-(C=0)-(Ci-C6)alkyl-(0=S=0)-(Ci-C6)alkyl, carboxy, Rn-(0=S=0)-, Rn-(0=S=0)-0- eller (Ci-Ce)alkoxy-(Ci-Ce)alkoxy; eller R4og R8, bundet til naboliggende kulstofringatomer, danner sammen med de kulstofringatomer, de er bundet til, en kondenseret fenylring, hvor nævnte fenylring er usubstitueret eller substitueret med 1 eller 2 substituent(er), idet hver uafhængigt er hydroxy, (CrC6)alkyl, (CrC6)alkoxy, hydroxy(Ci-C6)alkyl, halo(Cr C6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkyl-(C=0)- eller (Cr C6)alkoxy-(C=0)-; eller R4 og R8, bundet til naboliggende kulstofringatomer, danner sammen med de kulstofringatomer, de er bundet til, en kondenseret 5- eller 6-leddet mættet eller umættet carbocyklisk ring eller en kondenseret 5- eller 6-leddet mættet eller umættet heterocyklisk ring, der indeholder 1 eller 2 heteroatom(er), valgt blandt N, O og S, hvor nævnte carbocykliske eller heterocykliske ring er usubstitueret eller substitueret med 1 eller 2 substituent(er), idet hver uafhængigt er hydroxy, (CrC6)alkyl, (CrC6)alkoxy, hydroxy(Ci-Ce)alkyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkyl-(C=0)-, (Cr C6)alkoxy-(C=0)- eller oxo; eller R7 og R8 danner sammen med det kulstofringatom, de er bundet til, en 5- eller 6-leddet mættet carbocyklisk ring eller en 5- eller 6-leddet mættet heterocyklisk ring, der indeholder 1 eller 2 heteroatom(er), valgt blandt N, O og S, hvor nævnte carbocykliske eller heterocykliske ring er usubstitueret eller substitueret med 1 eller 2 substituent(er), idet hver uafhængigt er hydroxy, (Ci-C8)alkyl eller oxo; Rg er, ved hver forekomst, uafhængigt hydroxy, (Ci-C8)alkyl, (C2-C6)alkenyl, (Ci-Ce)alkoxy, halogen, hydroxy(Ci-C8)alkyl, halo(Ci-C8)alkyl, hydroxy(C2-C6)alkenyl, hydroxy(Ci-C8)alkoxy, halo(Ci-C8)alkoxy, fenyl(Ci-C6)alkoxy, (C1 -Ce)alkoxy(Ci-Ce)alkyl, (C2-Ce)alkenyloxy(Ci-C6)alkyl, (Ci-C6)alkyl-(C=0)-, (CrC6)alkoxy-(C=0)-, (Ci-C8)alkoxy-(C=0)-(Ci-C6)alkyl, (Ci-C6)alkyl-S-, (Ci-C6)alkyl-(C=0)-0-, (Ci-C6)alkyl-(C=0)-0-(Ci-C6)alkyl, hydroxy-(C=0)-(Ci-C6)alkoxy, hydroxy-(C=0)-(Cr C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxy-(C=0)-(Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkyl-S-(CrC6)alkyl, hydroxy(Ci-C6)alkyl-S-(Ci-C6)alkyl, (C1-C6)al koxy(Ci-C6)alkyl-S-(Ci-C6)alkyl, (C1 -C6)alkyl-(C=0)-S-(Ci -C6)alkyl, (C1 -C6)alkoxy-(C=0)-(Ci-C6)alkyl-S-(Ci-C6)alkyl, (Ci-C6)alkyl-S-(Ci- C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl-S-(Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)al koxy(Ci-C6)alkyl-S-(Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-Ce)alkyl-(0=S=0)-(Ci-C6)alkyl. hydroxy(Ci-C6)alkyl-(0=S=0)-(Ci-C6)alkyl, (Cr C6)alkoxy(Ci-C6)alkyl-(0=S=0)-(Ci-C6)alkyl> (Ci-C6)alkyl-(0=S=0)-(Ci-C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl-(0=S=0)-(Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl-(0=S=0)-(Ci-C6)alkoxy(Ci-C6)alkyl (Ci-C6)alkyl-0-(0=S=0)-(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl-0-(0=S=0)-(CrC6)alkyl, (Ci-C6)alkyl-(0=S=0)-0-(Ci-C6)alkyl, hydroxy(Ci-Ce)alkyl-(0=S=0)-0-(Ci-C6)alkyl, (Ci-C6)alkyl-(0=S=0)-N(Rio)-(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkoxy(Cr C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl, CN, NO2, (Rio)2N-, (Rio)2N-(Cr C6)alkyl, (Ri0)2N-(C=O)-, (Rio)2N-(C=0)-(Ci-C6)alkoxy(Ci-C6)alkylJ (Rio)2N-(C=0)-(Ci-C6)alkyl-S-(Ci-C6)alkyl,(Rio)2N-(C=0)-(Ci-C6)alkyl-(0=S=0)-(Ci-C6)alkyl, carboxy, Rn-(0=S=0)- eller Rn-(0=S=0)-0-; eller Rg og Rg, bundet til naboliggende kulstofringatomer, danner sammen med de kulstofringatomer, de er bundet til, en kondenseret fenylring, en kondenseret 5- eller 6-leddet umættet carbocyklisk ring eller en kondenseret 5- eller 6-leddet umættet heterocyklisk ring, der indeholder 1 eller 2 heteroatom(er), valgt blandt O og S, hvor nævnte fenylring, carbocykliske ring eller heterocykliske ring er usubstitueret eller substitueret med 1 eller 2 substituent(er), idet hver uafhængigt er hydroxy, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, hydroxy(Ci-Ce)alkyl, halo(Cr C6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkyl-(C=0)- eller (Cr C6)alkoxy-(C=0)-; R10 er, ved hver forekomst, uafhængigt H, (Ci-Ce)alkyl, hydroxy(Cr C6)alkyl, (Ci-C6)alkyl-(C=0)- eller Rn-(0=S=0)-; R11 er, ved hver forekomst, uafhængigt hydroxy, (Ci-Ce)alkyl, (C1-C6)alkoxy, halo(Ci-Ce)alkyl eller mono- eller di(Ci-C6)alkylamino; m er 0, 1 eller 2; og n er 1 eller 2; eller et(en) farmaceutisk acceptabel(t) salt eller ester deraf; underforudsætning af, at forbindelsen ikke er 1-(7-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,3-dimethyl-piperidin, 1 -(6-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,3-dimethyl-piperidin, 2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-6,7-dimethoxy-1 -methyl-1,2,3,4-tetrahydro-isokinolin, 2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isokinolin, 2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4-tetrahydro-isokinolin eller 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl-3-(3-trifluormethyl-fenyl)-pyrrolidin.
2. Forbindelse ifølge krav 1, hvor Z er -[C(R4)2]n- og n er 1.
3. Forbindelse ifølge et hvilket som helst af krav 1 eller 2, hvor R2 er H, R3 er H, og R4 er, ved hver forekomst, uafhængigt H, hydroxy eller (Ci-Ce)alkyl.
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor m er 0; eller hvor m er 1, og Ri er hydroxy, (Ci-C6)alkyl, (Ci-C6)alkoxy eller halogen.
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor X er C(R5)(R6); og/eller hvor R5 er H; og/eller hvor R6 er fenyl, substitueret med 1 substituent R9; og R9 er hydroxy, (Cr C6)alkyl, (Ci-Ce)alkoxy, halogen, hydroxy(Ci-Ce)alkoxy eller (Rio)2N-.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor X er C(R7)(R8); og/eller hvor R7 er (Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, (Ci-C6)alkoxy(CrC6)alkyl eller (C1-C6)alkoxy-(C=0)-; og/eller hvor R8 er hydroxy(Ci-C6)alkyl, hydroxy(Ci-Ce)alkoxy, (Ci-C6)alkoxy(CrC6)alkyl eller hydroxy(Ci -C8)al koxy(Ci -C8)al kyl.
7. Forbindelse ifølge krav 1, hvor Xer C(R5)(R6) eller C(R7)(R8); Z er -[C(R4)2]n- eller en enkeltbinding; Ri er, ved hver forekomst, uafhængigt hydroxy, (Ci-C8)alkyl, (Ci-C8)alkoxy, halogen, fenyl(Ci-C8)alkoxy eller NO2; R2 er, ved hver forekomst, uafhængigt H; R3 er, ved hver forekomst, uafhængigt H; R4 er, ved hver forekomst, uafhængigt H, hydroxy eller (Ci-C8)alkyl; eller R4 og R4, begge bundet til det samme kulstofringatom, danner sammen med det kulstofringatom, de er bundet til, en -(C=0)- gruppe; R5 er H; eller R4 og R5, bundet til naboliggende kulstofringatomer, danner en binding mellem de kulstofringatomer, de er bundet til; R6 er fenyl, usubstitueret eller substitueret med 1 eller 2 substituent(er) R9; R7 er (Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, (Ci-C6)alkoxy(CrC6)alkyl eller (C1-C6)alkoxy-(C=0)-; R8 er hydroxy, (Ci-Ce)alkyl, (C2-C8)alkenyl, (Ci-Ce)alkoxy, halogen, hydroxy(Cr C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C8)alkoxy, (Ci-C6)alkoxy(CrC6)alkyl, (C2-C6)alkenyloxy(CrC6)alkyl, (Ci-C6)alkyl-(C=0)-, (CrC6)alkoxy-(C=0)-, (C1-C6)alkoxy-(C=0)-(Ci-C6)alkyl, (Ci-C6)alkyl-(C=0)-0-(Ci-C6)alkyl, hydroxy-(C=0)-(Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)alkoxy-(C=0)-(Ci-C6)alkoxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl-S-(Ci-C6)alkyl, (Ci-C6)alkyl-(C=0)-S-(Ci-C6)alkyl, (Ci-C6)alkyl-(0=S=0)-0-(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy(Ci-C6)alkyl, (C1-C6)alkoxy(Ci-C6)alkoxy(Ci-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl, CN, (Rio^N-(CrC6)alkyl, (R10)2N-(C=O)-, carboxy eller (Ci-C6)alkoxy-(CrC6)alkoxy; eller R4 og R8, bundet til naboliggende kulstofringatomer, danner sammen med de kulstofringatomer, de er bundet til, en kondenseret fenylring, hvor nævnte fenylring er usubstitueret eller substitueret med 1 eller 2 substituent(er), idet hver uafhængigt er hydroxy(Ci-C8)alkyl eller (CrC6)alkoxy-(C=0)-; eller R4 og R8, bundet til naboliggende kulstofringatomer, danner sammen med de kulstofringatomer, de er bundet til, en kondenseret 6-leddet mættet carbocyklisk ring, hvor nævnte carbocykliske er usubstitueret; Rg er, ved hver forekomst, uafhængigt hydroxy, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halogen, hydroxy(Ci-C6)alkyl, halo(Ci-C6)alkyl, hydroxy(Ci-C6)alkoxy, halo(Cr C6)alkoxy, fenyl(Ci-C6)alkoxy, (CrC6)alkoxy-(C=0)-, (Ci-C6)alkyl-(C=0)-0-, hydroxy-(C=0)-(Ci-C6)alkoxy, CN, (Ri0)2N-, (Rio)2N-(C=0)-, Rn-(0=S=0)- eller Rii-(0=S=0)-0-; eller Rg og Rg, bundet til naboliggende kulstofringatomer, danner sammen med de kulstofringatomer, de er bundet til, en kondenseret 5- eller 6-leddet umættet heterocyklisk ring, der indeholder 1 eller 2 heteroatom(er), valgt blandt O, hvor nævnte fenylring, carbocykliske ring eller heterocykliske ring er usubstitueret; Rio er, ved hver forekomst, uafhængigt H eller (CrC6)alkyl, R11 er, ved hver forekomst, uafhængigt (Ci-Ce)alkyl eller halo(Ci-Ce)alkyl; m er 0, 1 eller 2; og n er 1 eller 2.
8. Forbindelse ifølge krav 7, hvor Xer C(R5)(R6) eller C(R7)(R8); Z er -[C(R4)2]n-; Ri er, ved hver forekomst, uafhængigt hydroxy, (Ci-Ce)alkyl, eller halogen; R2 er, ved hver forekomst, uafhængigt H; R3 er, ved hver forekomst, uafhængigt H; R4 er, ved hver forekomst, uafhængigt H; Rs er H; R6 erfenyl, usubstitueret eller substitueret med 1 eller 2 substituent(er) Rg; R7 er (Ci-Ce)alkyl; Rs er hydroxy(Ci-C6)alkyl, hydroxy(Ci-Ce)alkoxy, (Ci-C6)alkoxy(CrC6)alkyl eller hydroxy(Ci-C6)alkoxy(Ci-C6)alkyl; Rg er, ved hver forekomst, uafhængigt hydroxy, (Ci-C6)alkyl, (Ci-C6)alkoxy, halogen, hydroxy(Ci-Ce)alkoxy eller (Rio)2N-; Rio er, ved hver forekomst, uafhængigt H eller (CrC6)alkyl; m er 0 eller 1; n er 1.
9. Forbindelse ifølge krav 7, hvor X er C(R5)(R6) eller C(R7)(R8); Z er en enkeltbinding; Ri er, ved hver forekomst, uafhængigt hydroxy, (Ci-Ce)alkyl eller halogen; R2 er, ved hver forekomst, uafhængigt H; R3 er, ved hver forekomst, uafhængigt H; R4 er, ved hver forekomst, uafhængigt H; R5 er H; R6 erfenyl, usubstitueret eller substitueret med 1 eller 2 substituent(er) R9; R7 er (Ci-Ce)alkyl; Rs er hydroxy(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkoxy, (Ci-C6)alkoxy(CrC6)alkyl eller hydroxy(Ci-C6)alkoxy(Ci-C6)alkyl; Rg er, ved hver forekomst, uafhængigt hydroxy, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, halogen, hydroxy(Ci-Ce)alkoxy eller (Rio)2N-; R10 er, ved hver forekomst, uafhængigt H eller (Ci-Ce)alkyl; m er 0 eller 1; n er 1.
10. Forbindelse ifølge krav 1, hvor forbindelsen er 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-5-fenyl-1,2,3,6-tetrahydropyridin, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fenylpiperidin, 1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(2-methoxyfenyl)piperidin, 3-(4-klorfenyl)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin, 1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(3-methoxyfenyl)piperidin, 1 -(2,3-dihydrobenzo[1,4]dioxiri-2-ylmethyl)-3-p-tolylpiperidin, 1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(4-methoxyfenyl)piperidin, 1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-o-tolylpiperidin, 4-[1 -(2,3- dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]fenol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(3-fluorfenyl)piperidin, 3-[1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]fenol, 2-[1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]fenol, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-fluorfenyl)piperidin, (S*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-fluorfenyl)piperidin, (R*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorfenyl)piperidin, (R*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorfenyl)piperidin HCI, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorfenyl)piperidin, (R*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-fluorfenyl)piperidin, (S*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-fluorfenyl)piperidin, (R*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-trifluormethylfenyl)piperidin, (S*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-trifluormethyl-fenyl)piperidin, (R*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-trifluormethylfenyl)piperidin, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-trifluormethylfenyl)piperidin, (R*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyfenyl)piperidin, (R*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyfenyl)piperidin -HCI, (S*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyfenyl)piperidin, (R*)-3-{1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}fenol, (R*)-3-{1 -[(iS)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}fenol -HCI, (3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}fenyl)methanol, eddikesyre-3-{(S)-1 -[(R*)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}fenylester HCI, 2-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}fenoxy)ethanol, 3-(3-{(R*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}fenoxy)propan-1 -ol, trifluormethansulfonsyre 3-{(R*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}fenylester, (3-{(R*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}fenoxy)eddikesyre, 3-{(R*)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}-benzonitril, 3-benzo[1,3]dioxol-5-yl-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin, 3-[(R*)-1 -((S)-6-benzyloxy-2,3- dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-fenol, (S)-2-[(R*)-3-(3-hydroxy-fenyl)-piperidin-1 -ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-6-ol, 3-[(R*)-1 -((S)-7-benzyloxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-fenol, (S)-3-[(R*)-3-(3-hydroxy-fenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-6-ol, 3-[(R*)-1-((S)-8-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]fenol, (S)-3-[(R*)-3-(3-hydroxy-fenyl)-piperidin-1-ylmethyl]-2,3-dihydrobenzo[1,4]dioxin-5-ol, (R*)-3-[1 -((S)-7-fluor-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]fenol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-carboxylsyre-ethylester, 1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-carboxylsyre-ethylester, [1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidin, 1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethoxymethyl-3-methylpiperidin, 3-klormethyl-1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin, 2-[1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]propan-2-ol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(1 -methoxy-1 -methylethyl)-3-methylpiperidin, 1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-hydroxymethyl-3-methylpiperidin-4-ol, eddikesyre 1-(2,3dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethylester, methansulfonsyre 1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethylester, [1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]methanol, 1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethyl-3-methoxymethylpiperidin, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethoxymethyl-3-methylpiperidin, 1 -[1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanon, 1 -[1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanol, 3-allyloxymethyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin, 2-[1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl-methoxy]ethanol, 3-allyloxymethyl-1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin, 3-allyl-1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidin-3-carboxylsyreethylester, [3-allyl-1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]methanol, 3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2- ylmethyl)-3-methoxymethylpiperidin, 3-allyl-1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethoxymethylpiperidin, 1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-3-(2,2,2-trifluorethoxymethyl)-piperidin, 2-[1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethoxy]ethanol, (S)- 1- ((R)-2,3-dihydrobenzo[1,4]dioxin-2-carbonyl)-3-methylpiperidin-3-carboxylsyreethylester, lithium (S)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidin-3-carboxylat, {(S)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}methanol, 2-{(S)-1 -[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanol, 2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl1-3-methylpiperidin-3-ylmethoxy}-ethanol D-tartrat, (S)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxyethoxymethyl)-3-methylpiperidin, (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-3-(2,2,2-trifluorethoxymethyl)piperidin, methansulfonsyre (S)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidin-3-ylmethylester, thioeddikesyre S-{(S)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethyl} ester, 2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin- 2- yl)methyl]-3-methylpiperidin-3-ylmethyl-sulfanyl}ethanol, {(S)-1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}eddikesyre tert-butyl ester, natrium {(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]- 3- methylpiperidin-3-yl-methoxy}acetat, 2-[(S)-1-((S)-7-fluor-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl-methoxy]ethanol, 1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluor-piperidin-3-carboxylsyreethylester, [1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluor-piperidin-3-yl]methanol, (S)-1 -[(S)-1 -(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-methyl-ylmethyl)-3-methylpiperidin-3-yl-methoxy]ethanol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluor-piperidin-3-carboxylsyreethylester, [1 -(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluor-piperidin-3-yl]methanol, (S)-1 -[(S)-1 -(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidin-3-carboxylsyreethylester, [(S)-1 -((S)-7-fluor-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin-3-yl]-methanol, (S)-1-((S)-7-fluor-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-piperidin, (S)-1 -((S)-7- fluor-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-piperidin HCI, (S)-1-[(S)-1-(2,3-dihydro-benzo[1,4]-dioxin-2-yl)methyl]-3-methoxymethyl-3-methyl-piperidin, 3-{(R*)-1 -[(S)-1 -(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}-fenylamin, (R*)-3-{1 -[(S)-1 -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}fenoloxalat, (S)-2-[(R*)-3-(3-hydroxy-fenyl)-piperidin-1-ylmethyl]-2,3-dihydro-benzo[1,4]dioxin-5-ol, 1-[(S)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxy-fenyl)-pyrrolidin, (S)-1 -[(S)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-(2-fluor-ethoxymethyl)-3-methyl-piperidin -HCI, (R*)-1-[(S)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl]-3-(3-fluormethoxy-fenyl)-piperidin, 1 -(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-carboxylsyremethylester, [1 -(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-yl]-methanol, 2-[1 -(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-ylmethoxy]-ethanol, 1 -(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-pyrrolidin eller 3-[(R)-1-((S)-7-nitro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-fenol.
11. Forbindelse ifølge krav 1, hvor forbindelsen er (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorfenyl)piperidin eller et farmaceutisk acceptabelt salt deraf.
12. Forbindelse ifølge krav 1, hvor forbindelsen er (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyfenyl)piperidin eller et farmaceutisk acceptabelt salt deraf.
13. Forbindelse ifølge krav 1, hvor forbindelsen er (R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}fenol eller et farmaceutisk acceptabelt salt deraf.
14. Forbindelse ifølge krav 1, hvor forbindelsen er (3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}fenyl)methanol eller et farmaceutisk acceptabelt salt deraf.
15. Forbindelse ifølge krav 1, hvor forbindelsen er 2-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}fenoxy)ethanol eller et farmaceutisk acceptabelt salt deraf.
16. Forbindelse ifølge krav 1, hvor forbindelsen er 3-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}fenoxy)propan-1 -ol eller et farmaceutisk acceptabelt salt deraf.
17. Forbindelse ifølge krav 1, hvor forbindelsen er (R*)-3-[1-((S)-7-fluor-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]fenol eller et farmaceutisk acceptabelt salt deraf.
18. Forbindelse ifølge krav 1, hvor forbindelsen er {(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}methanol eller et farmaceutisk acceptabelt salt deraf.
19. Forbindelse ifølge krav 1, hvor forbindelsen er 2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanol eller et farmaceutisk acceptabelt salt deraf.
20. Forbindelse ifølge krav 1, hvor forbindelsen er (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxyethoxymethyl)-3-methylpiperidin eller et farmaceutisk acceptabelt salt deraf.
21. Forbindelse ifølge et hvilket som helst af kravene 1 til 20 til anvendelse som et lægemiddel.
22. Forbindelse ifølge et hvilket som helst af kravene 1 til 20 til anvendelse i behandlingen af en sygdom eller en tilstand, hvor en alpha2C-antagonist er indiceret som anvendelig.
23. Forbindelse til anvendelse ifølge krav 22, hvor sygdommen eller tilstanden er en gennem stress forstærket sindslidelse, Parkinsons sygdom, depression, skizofreni, ADHD, posttraumatisk stresslidelse, obsessiv-kompulsiv tilstand (OCD), Tourettes syndrom, blefarospasme eller andre fokale dystonier, temporallapsepilepsi med psykose, en lægemiddelinduceret psykose, Huntingtons sygdom, en forstyrrelse, der forårsages af udsving i kønshormonniveauer, panikangst, Alzheimers sygdom eller let kognitiv svækkelse (MCI).
24. Farmaceutisk sammensætning, der omfatter i det mindste en forbindelse ifølge et hvilket som helst af kravene 1 til 20 og en(et) farmaceutisk acceptabel(t) bærer, fortyndingsmiddel og/eller excipiens.
25. Farmaceutisk sammensætning ifølge krav 24, hvor sammensætningen endvidere omfatter i det mindste et andet aktivt stof.
DK08787689.2T 2007-07-20 2008-07-18 2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl-derivater som alpha2c-antagonister til anvendelse i behandlingen af sygdomme i det perifere nervesystem og centralnervesystemet DK2176252T3 (da)

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