DK2834233T3 - Nye alpha2 adrenoceptor-agonister - Google Patents

Nye alpha2 adrenoceptor-agonister Download PDF

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DK2834233T3
DK2834233T3 DK13719297.7T DK13719297T DK2834233T3 DK 2834233 T3 DK2834233 T3 DK 2834233T3 DK 13719297 T DK13719297 T DK 13719297T DK 2834233 T3 DK2834233 T3 DK 2834233T3
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dihydro
imidazole
methylisochroman
alkyl
hydrochloride
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Tuula Koskelainen
Tero Linnanen
Anna Minkkilä
Mikko Mäkelä
Antti Pohjakallio
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Orion Corp
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Claims (10)

1. Forbindelse, der er med formlen I,
hvor X er O eller S; Ri er hydroxy, halogen, (Ci-C6)-alkyl, halo(Ci-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, cyclo(C3-C6)-alkyl, (Ci-C6)-alkoxy, halo(Ci-C6)-alkoxy, hydroxy(Ci-C6)-alkyl, cyano, (R6)2N-(C=0)-, (Ci-C6)-alkyl-S-, eller heteroarylgruppe, der er et 3- til 7-leddet aromatisk monocyklisk ringsystem, der indeholder ét til tre heteroatom(er) udvalgt fra oxygen, nitrogen og svovl, hvilken heteroaryl kan være usubstituereteller substitueret med 1 eller 2 substituent(er), der hver uafhængigt er hydroxy, halogen, oxo, (Ci-C4)-alkyl, (Ci-C4)-alkoxy eller halo(Ci-C4)-alkyl; R2 er H eller (Ci-C6)-alkyl; R3 er H, (Ci-C6)-alkyl, halo(Ci-C6)-alkyl eller (Ci-C6)-alkoxy(Ci-C6)- alkyl; R4 er H eller (Ci-C2)-alkyl; R5 er H, hydroxy, halogen, (Ci-C6)-alkyl, eller (Ci-C6)-alkoxy; R6 er H; eller Ri og R2 danner, sammen med de carbonringatomer, hvortil de er bundet en kondenseret 6- eller 7-leddet, mættet eller umættet carbocyklisk ring, hvor den carbocykliske ring er usubstitueret eller substitueret med 1 eller 2 substituent(er), der hver uafhængigt er hydroxy, oxo, halogen, (Ci-C2)-alkyl, (Ci-C2)-alkoxy, hydroxy(Ci-C2)-alkyl eller halo(Ci-C2)-alkyl; eller er et farmaceutisk acceptabelt salt deraf.
2. Forbindelse ifølge krav 1, hvor Ri er hydroxy, halogen, (C1-C3)-alkyl, halo(Ci-C3)-alkyl, (Ci-C3)-alkoxy, halo(Ci-C3)-alkoxy eller hydroxy(Ci-C3)-alkyl; og/eller R2 er H eller (Ci-C2)-alkyl; og/eller R3 er H, (Ci-C3)-alkyl eller halo(Ci-C3)-alkyl; og/eller R4 er H eller methyl; og/eller R5 er H, halogen eller (Ci-C2)-alkyl; og/eller R1 0g R2 danner, sammen med det carbonringatomer, hvortil de er bundet, en kondenseret 6- eller 7-leddet mættet eller umættet carbocyklisk ring.
3. Forbindelse ifølge et hvilket som helst af kravene 1 eller 2, hvor Ri er halogen, (Ci-C2)-alkyl, halo(Ci-C2)-alkyl, (Ci-C2)-alkoxy eller halo(Ci-C2)-alkoxy; og/eller R2 er H; og/eller R3 er H eller (Ci-C2)-alkyl; og/eller R4 er H; og/eller R5 er H.
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor X er O.
5. Forbindelse ifølge krav 1, hvor forbindelsen er 2-(5-methylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-bromisochroman-1 -yl)- 4,5-dihydro-1H-imidazol, 2-(1,5-dimethylisochroman-1-yl)-4,5-dihydro-1H-imidazol, 2-(5-chlorisochroman-1-yl)-4,5-dihydro-1H-imidazol, 1-(4,5-dihydro-1 H-imidazol-2-yl)isochroman-5-carbonitril, 2-(5-allylisochroman-1 -yl)-4,5- dihydro-1H-imidazol, 2-(5-vinylisochroman-1-yl)-4,5-dihydro-1H-imidazol, 2-(5-ethylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-ethylisochroman-1 -yl)-4,5-dihydro-1H-imidazolhydrochlorid, 2-(5-ethylisochroman-1-yl)-4,5-dihydro-1H-imidazolsulfat, 2-(5-ethylisochroman-1 -yl)-4,5-dihydro-1 H-imidazolfumarat, 1 -(4,5-dihydro-1H-imidazol-2-yl)isochroman-5-ol, (1-(4,5-dihydro-1H-imidazol-2-yl)iso-chroman-5-yl)methanol, 2-(5-brom-1 -methylisochroman-1 -yl)-4,5- dihydro-1 H-imidazol, 2-((3R)-5-chlor-3-ethylisochroman-1-yl)-4,5-dihydro-1H-imidazol, langsommere eluerende isomer af 1-(1-(4,5-dihydro-1 H-imidazol-2-yl)-1-methyl-isochroman-5-yl)-2,2-dimethylpropan-1-ol, hurtigere eluerende isomer af 1 -(1 -(4,5-dihydro-1 H-imidazol-2-yl)-1 -methyliso-chroman-5-yl)-2,2-dimethylpropan-1-ol, 2-(5-ethynylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-((3R)-3-ethyl-5-(trifluormethyl)isochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-methoxyisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazolhydrochlorid, 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1 H-imidazolsulfat, 2-(5-methoxyisochroman-1 -yl)-4,5-dihydro-1 H- imidazolhemifumarat, 2-(5-iodisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-((3R)-3-methyl-5-(trifluormethyl)isochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-(5-brom-4-methylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, hurtigere eluerende isomer af 2-(1,5-dimethylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, langsommere eluerende isomer af 2-(1,5-dimethylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-((3R)-1,3,5-trimethylisochroman-1-yl)-4,5-dihydro-1H-imidazol, 2-(5-cyclopropylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(3,5-dimethylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-chlor-3- methylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(3-ethyl-5- methylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-(5-chlor-1,3- dimethylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-brom-3- methylisochroman-1 -yl)-4,5-di-hydro-1 H-imidazol, 2-(1,3,5- trimethylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-brom-1,3-dimethyliso-chroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-((3F?)-5-brom-3-methylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-((3f?)-5-chlor-3-methylisochroman-1-yl)-4,5- dihydro-1 H-imidazol, 2-((3S)-5-chlor-3-methylisochroman-1-yl)-4,5-dihydro-1H-imidazol, 2-((3S)-5-brom-3-methylisochroman-1 -yI)-4,5-dihydro-1 H-imidazol,2-((3R)-3,5-dimethylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-((3S)-3,5-dimethylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-methoxy-3- methylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-ethyl-3- methylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-brom-3- propylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-isopropylisochroman-1 -yl )-4,5-d i hyd ro-1 H-imidazol, 2-(5-fluorisochroman-1-yl)-4,5-dihydro-1H- imidazol, 2-(5-brom-3-ethylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-((3R)-5-methoxy-3-methylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-((3R)-5-ethyl-3-methylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-((3R)-5-ethyl-3- methylisochroman-1-yl)-4,5-dihydro-1H-imidazolhydrochlorid, 2-((3R)-5-ethyl-3-methylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol-hemifumarat, 2-(3-ethyl-5-methoxyisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-((3R)-3,5- diethylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-((3R)-3-ethyl-5- methylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-((3R)-3-ethyl-5- methylisochroman-1-yl)-4,5-dihydro-1/-/-imidazolhydrochlorid, 2-((3R)-3-ethyl-5-methylisochroman-1 -yl)-4,5-di-hydro-1 H-imidazolsulfat, 2-((3R)-3-ethyl-5-methylisochroman-1 -yl)-4,5-dihydro-1 H-imidazolhemifumarat, 2-((3R)-3- methyl-5-(trifluormethoxy)isochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-((3R)-5-fluor-3-methyliso-chroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5- ethoxyisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-(5-methyl-3-(2,2,2- trifluorethyl)isochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-((3S)-5-methoxy-3-methylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-(5-(furan-3-yl)isochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-(prop-1 -yn-1 -yl)iso-chroman-1 -yl)-4,5- dihydro-1 H-imidazol, 1 -(4,5-dihydro-1 H-imidazol-2-yl)isochroman-5- carboxamid, 2-(3,7,8,9,10,10a-hexahydro-1 H-cyclohepta[de]isochromen-3-yl)- 4,5-dihydro-1 H-imidazol, langsomt eluerende isomer af 1-(1-(4,5-dihydro-1H-imidazol-2-yl)isochroman-5-yl)ethanol, 2-(5,7-dimethylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-(7-brom-5-methylisochroman-1-yl)-4,5-dihydro-1H-imidazol, 2-(7-methoxy-5-methylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-(3,5-dimethylisothiochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-(5-brom-3-methylisothiochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5- methylisothiochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5- bromoisothiochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-brom-1 - methylisothiochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5,7-dibrom-3- ethylisochroman-1-yl)-4,5-dihydro-1H-imidazolhydrochlorid, enantiomer af 2-5-brom-3-(2,2,2-trifluorethyl)isochroman-1 -yl)-4,5-dihydro-1H-imidazolhydrochlorid, 2-(5-methoxy-1-methylisochroman-1-yl)-4,5-dihydro-1H-imidazol, 2-(5-methoxyisothiochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-((3R)-5-methoxy-1,3-dimethylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-(2,2,2-trifluorethyl)isochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-((3R)-5-ethyl-1,3-dimethylisochroman-1 -yl)-4,5-dihydro-1 H-imidazol, 2-(5-methyl-3- (methoxymethyl)isochroman-1-yl)-4,5-dihydro-1 H-imidazol, 1-(4,5-dihydro-1H-imidazol-2-yl)-5-methylisochroman-7-ol-hydrobromid, 1 -(4,5-dihydro-1 H-imidazol-2-yl)-3-ethylisochroman-5-ol-hydrochlorid, enantiomer-2 af 2-(5-methoxy-3-(2,2,2-trifluorethyl)methylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-(1,5-dimethylisothiochroman-1-yl)-4,5-dihydro-1 H-imidazol, 2-(5- (trifluormethoxy)isochroman-1-yl)-4,5-dihydro-1H-imidazolhydrochlorid, enantiomer-1 af 2-(3-ethylisochroman-1-yl)-4,5-dihydro-1H- imidazolhydrochlorid, 2-(3-(2-fluorethyl)-5-methylisochroman-1-yl)-4,5-dihydro-1H-imidazolhydrochlorid, enantiomer af 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1 H-imidazol, enantiomer-2 af 2-5-brom-3-(2,2,2- trifluorethyl)isochroman-1 -yl)-4,5-dihydro-1 H-imidazolhydrochlorid, 2-(3-(2,2-difluorethyl)-5-methylisochroman-1 -yl)-4,5-dihydro-1 H-imidazolhydrochlorid, 2-(7-methoxy-3,5-dimethylisochroman-1-yl)-4,5-dihydro-1 H-imidazol, enantiomer-2 af 2-((3)-5-methyl-3-(2,2,2-trifluorethyl)isochroman-1 -yl)-4,5-dihydro-1 H-imidazolhydrochlorid, 2-(5-(methylthio)isochroman-1-yl)-4,5- dihydro-H-imidazol, enantiomer-2 af 2-((3)-5-brom-3-propylisochroman-1-yl)- 4,5-dihydro-1 H-imidazolhydrochlorid, enantiomer-2 af 2-((3R)-3-(2,2-difluorethyl)-5-methylisochroman-1 -yl)-4,5-dihydro-1 H-imidazolhydrochlorid, 2-(5-(difluormethoxy)isochroman-1 -yl)-4,5-dihydro-1 H-imidazolhydrochlorid, 2-((3R)-3-ethyl-5-methoxyiso-chroman-1-yl)-4,5-dihydro-1 H-imidazol, enantiomer-1 af 2-(5-chlorisochroman-1-yl)-4,5-dihydro-1H- imidazolhydrochlorid, 2-((3R)-5-(difluormethoxy)-3-methylisochroman-1-yl)-4,5-dihydro-1 H-imidazolhydrochlorid, enantiomer af 2-(5-brom-3-ethylisochroman- 1-yl)-4,5-dihydro-1H-imidazol, enantiomer-1 af 2-(5-chlorisochroman-1-yl)-4,5-dihydro-1H-imidazolhydrochlorid, enantiomer-2 af 2-(3-ethylisochroman-1-yl)- 4.5- dihydro-1H-imidazol, enantiomer-2 af 2-(5-methoxyoisochroman-1-yl)-4,5- dihydro-1 H-imidazolhydrochlorid, 2-(1 -methyl-1,3- dihydrobenzo[de]isochromen-1-yl)-4,5-dihydro-1H-imidazol, 2-(5- (difluormethyl)isochroman-1-yl)-4,5-dihydro-1 H-imidazolhydrochlorid, enantiomer-2 af 2-(5-chlorisochroman-1-yl)-4,5-dihydro-1H- imidazolhydrochlorid, enantiomer-2 af 2-(5-bromisochroman-1-yl)-4,5-dihydro-1 H-imidazolhydrochlorid, 2-(1,3-dihydrobenzo[de]isochromen-1-yl)-4,5- dihydro-1 H-imidazolhydrochlorid, enatiomer af 2-(1-methyl-1,3- dihydrobenzo[de]isochromen-1-yl)-4,5-dihydro-1H-imidazol, 2-(3-methyl-1,3-dihydrobenzo[de]isochromen-1-yl)-4,5-dihydro-1 H-imidazolhydrochlorid, 2-(3-ethyl-1,3-dihydrobenzo[de]isochromen-1 -yl)-4,5-dihydro-1 H-imidazolhydrochlorid eller enantiomer af 2-(5-brom-1-methylisochroman-1-yl)- 4.5- dihydro-1 H-imidazol.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5 til anvendelse som et medikament.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 6 til anvendelse i behandlingen af en forstyrrelse, tilstand eller sygdom, hvor en alpha2-agonist er indikeret som anvendelig, hvor forstyrrelsen, tilstanden eller sygdommen er delirium, hyperaktivt delirium, søvnløshed, ADHD, benzodiazepin- eller alkohol- eller opioid- eller tobaksabstinenser, præmatur ejakulation, hypertension, takykardi, uro i benene, muskelspasticitet, hedeture, angst, posttraumatisk stressforstyrrelse, smerte, kronisk bækkensmertesyndrom, smerte ved gennembrud af cancer, eller tilstand, hvor sedation eller analgesi er nødvendig.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 6 til anvendelse i behandlingen af en forstyrrelse, tilstand eller sygdom hvor en alpha2-agonist er indikeret som anvendelig, hvor forstyrrelsen, tilstanden eller sygdommen er delirium, hyperaktivt delirium, søvnløshed, ADHD, benzodiazepin- eller alkohol- eller opioid- eller tobaksabstinenser, præmatur ejakulation, hypertension, takykardi, uro i benene, muskelspasticitet, hedeture, angst, posttraumatisk stressforstyrrelse, smerte, kronisk bækkensmertesyndrom, smerte ved gennembrud af cancer, eller tilstand, hvor sedation eller analgesi er nødvendig.
9. Farmaceutisk sammensætning, der omfatter mindst én forbindelse ifølge et hvilket som helst af kravene 1 til 5 og en farmaceutisk acceptabel bærer, fortynder og/eller excipiens.
10. Farmaceutisk sammensætning ifølge krav 9, hvor sammensætningen endvidere omfatter mindst ét andet aktivt indholdsstof.
DK13719297.7T 2012-04-02 2013-03-28 Nye alpha2 adrenoceptor-agonister DK2834233T3 (da)

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