HRP20220736T1 - Supstituirani azacikli kao pozitivni alosterički modulatori muskarinskog receptora m1 - Google Patents

Supstituirani azacikli kao pozitivni alosterički modulatori muskarinskog receptora m1 Download PDF

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HRP20220736T1
HRP20220736T1 HRP20220736TT HRP20220736T HRP20220736T1 HR P20220736 T1 HRP20220736 T1 HR P20220736T1 HR P20220736T T HRP20220736T T HR P20220736TT HR P20220736 T HRP20220736 T HR P20220736T HR P20220736 T1 HRP20220736 T1 HR P20220736T1
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methyl
pyridin
hydroxycyclohexyl
dihydropyrrolo
dihydro
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Ramakrishna Nirogi
Anil Karbhari Shinde
Abdul Rasheed Mohammed
Rajesh Kumar Badange
Raghava Choudary PALACHARLA
Venkateswarlu Jasti
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Suven Life Sciences Limited
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Claims (12)

1. Spoj formule (I), [image] ; pri čemu: R1 je -(C6-10)-aril, -(C5-10)-heteroaril ili -(C3-14)-nearomatski heterociklil; od kojih je svaki nesupstituiran ili supstituiran s jednim ili više supstituenata koje se bira između halogena, -OH, -O-(C1-6)-alkila, -S-(C1-6)-alkila, -N(CH3)2, -(C1-6)-alkila, -(C3-6)-cikloalkila, halogen(C1-6)-alkila, -NH2, -CN, -CONH2, -CONH-(C1-6)-alkila i R1a; R1a je -(C6-10)-aril, -(C5-10)-heteroaril ili -(C3-14)-nearomatski heterociklil; od kojih je svaki nesupstituiran ili supstituiran s jednim ili više supstituenata koje se bira iz skupine koju čine halogen, -OH, -NH2, -CN, -O-(C1-6)-alkil, -S-(C1-6)-alkil, -(C1-6)-alkil i -(C3-6)-cikloalkil; A1 je CH2 ili CHF; R2 je -(C1-6)-alkil; X1 je N; n je 1 ili 2; m je 0 ili 1; Y1 je CH2, O, NH ili NCH3; Y2 je CH2, O, NH ili NCH3; i Z je H, OH ili F; ili njegov izotopni oblik, stereoizomer, tautomer ili farmaceutski prihvatljiva sol.
2. Spoj u skladu s patentnim zahtjevom 1, pri čemu se spoj bira iz skupine koju čine: 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(4-pirazol-1-ilbenzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-[2-(1-metil-1H-pirazol-4-il)piridin-5-ilmetil]-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-[4-(1-metil-1H-pirazol-4-il)benzil]-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(4-tiazol-4-ilbenzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(2,3-difluorbenzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(4-metoksibenzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(2-metilpiridin-5-ilmetil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(2-fluorpiridin-4-ilmetil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(4-fluorbenzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(3-fluorbenzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(2-fluorpiridin-5-ilmetil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(2-klorpiridin-5-ilmetil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(4-hidroksitetrahidropiran-3-il)-3-(4-metoksibenzil)-2-metil-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(4-metoksibenzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(tetrahidropiran-4-il)-2-metil-3-[2-(1-metil-1H-pirazol-4-il)piridin-5-ilmetil]-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(tetrahidropiran-4-il)-2-metil-3-[4-(2-metil-oksazol-4-il)-benzil]-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(tetrahidropiran-4-il)-2-metil-3-(4-tiazol-4-ilbenzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(3-klorbenzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(3,4-difluorbenzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(2,3-difluorbenzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(3-klorbenzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-[4-(2-metil-oksazol-4-il)-benzil]-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-[4-klorbenzil]-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(3-metoksibenzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(6-metoksipiridin-3-ilmetil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(4-klorbenzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(4-hidroksitetrahidro-piran-3-il)-2-metil-3-[4-metoksibenzil]-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(2-fluorpiridin-4-ilmetil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(6-fluorpiridin-3-ilmetil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(2-klorpiridin-4-ilmetil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(4-hidroksitetrahidropiran-3-il)-2-metil-3-(4-pirazol-1-il-benzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(4-hidroksitetrahidropiran-3-il)-2-metil-3-[6-(1-metil-1H-pirazol-4-il)-piridin-3-ilmetil]-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(4,4-difluorpiperidin-1-ilmetil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 1-[6-(1S,2S-2-hidroksicikloheksil)-2-metil-5-okso-6,7-dihidro-5H-pirolo[3,4-b]piridin-3-ilmetil]-4-fenilpiperidin-4-karbonitril; 1-[6-(1S,2S-2-hidroksicikloheksil)-2-metil-5-okso-6,7-dihidro-5H-pirolo[3,4-b]piridin-3-ilmetil]-4-piridilpiperidin-4-karbonitril; 1-[6-(1S,2S-2-hidroksicikloheksil)-2-metil-5-okso-5,6,7,8-tetrahidro-[1,6]naftiridin-3-ilmetil]-4-fenilpiperidin-4-karbonitril; 6-(3-fluor-piperidin-4-il)-2-metil-3-(4-metoksibenzil)-6,7-dihidro-pirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(3-metoksibenzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(tetrahidro-piran-4-il)-2-metil-3-(4-metoksibenzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(1S,2S-2-hidroksicikloheksil)-2-metil-3-(3-fluorbenzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(tetrahidro-piran-4-il)-2-metil-3-(4-tiazol-4-ilbenzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(4-hidroksi-tetrahidro-piran-3-il)-2-metil-3-(4-pirazol-1-il-benzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(tetrahidro-piran-4-il)-2-metil-3-(3-metoksibenzil)-6,7-dihidropirolo[3,4-b]piridin-5-on; 6-(4-hidroksi-tetrahidro-piran-3-il)-2-metil-3-(4-metoksibenzil)-6,7-dihidro-pirolo[3,4-b]piridin-5-on-cis-izomer (1. eluirajući izomer, 1. signal); 6-(4-hidroksi-tetrahidro-piran-3-il)-2-metil-3-(4-metoksibenzil)-6,7-dihidro-pirolo[3,4-b]piridin-5-on-cis,cis-izomer (2. eluirajući izomer, 2. signal); 6-(tetrahidro-piran-4-il)-2-metil-3-(4-metoksibenzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(tetrahidro-piran-4-il)-2-metil-3-(4-pirazol-1-il-benzil)-6,7-dihidro-pirolo[3,4-b]piridin-5-on; 6-(tetrahidro-piran-4-il)-2-metil-3-(4-pirazol-1-il-benzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(4-hidroksi-tetrahidro-piran-3-il)-2-metil-3-(4-fluorbenzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; 6-(4-hidroksi-tetrahidro-piran-3-il)-2-metil-3-(3-fluorbenzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; i 6-(4-hidroksi-tetrahidro-piran-3-il)-2-metil-3-(2,3-difluorbenzil)-7,8-dihidro-6H-[1,6]naftiridin-5-on; ili njihove farmaceutski prihvatljive soli.
3. Spoj u skladu s patentnim zahtjevom 1 ili patentnim zahtjevom 2, pri čemu se farmaceutski prihvatljivu sol bira iz skupine koju čine: 1-[6-(1S,2S-2-hidroksicikloheksil)-2-metil-5-okso-6,7-dihidro-5H-pirolo[3,4-b]piridin-3-ilmetil]-4-piridilpiperidin-4-karbonitril-L-(+)-tartarat; 1-[6-(1S,2S-2-hidroksicikloheksil)-2-metil-5-okso-5,6,7,8-tetrahidro-[1,6]naftiridin-3-ilmetil]-4-fenil-piperidin-4-karbonitril-L-(+)-tartarat; i 6-(3-fluor-piperidin-4-il)-2-metil-3-(4-metoksibenzil)-6,7-dihidro-pirolo[3,4-b]piridin-5-on hidroklorid.
4. Farmaceutski pripravak koji sadrži spoj formule (I), ili njegovu farmaceutski prihvatljivu sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 3 i farmaceutski prihvatljiva pomoćna sredstva.
5. Farmaceutski pripravak u skladu s patentnim zahtjevom 4, namijenjen upotrebi u liječenju bolesti ili poremećaja kod kojeg posreduje muskarinski receptor M1, pri čemu se navedena bolest ili poremećaj bira iz skupine koju čine kognitivni poremećaji, Alzheimerova bolest, shizofrenija, bol ili poremećaj spavanja.
6. Spoj formule (I), ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 3, namijenjen upotrebi u postupku liječenja bolesti ili poremećaja kod kojeg posreduje muskarinski receptor M1, pri čemu bolest ili poremećaj se bira iz skupine koju čine kognitivni poremećaji, Alzheimerova bolest, shizofrenija, bol ili poremećaj spavanja.
7. Spoj namijenjen upotrebi u skladu s patentnim zahtjevom 6, pri čemu kognitivni poremećaj se bira iz skupine koju čine demencija kod Alzheimerove bolesti, demencija kod Parkinsonove bolesti, demencija kod Huntingtonove bolesti, demencija povezana s Downovim sindromom, demencija povezana s Touretteovim sindromom, demencija povezana s postmenopauzom, frontotemporalna demencija, demencija Lewyjevih tjelešaca, vaskularna demencija, demencija kod HIV-a, demencija kod Creutzfeldt-Jakobove bolesti, perzistirajuća demencija izazvana upotrebom tvari, demencija kod Pickove bolesti, demencija kod shizofrenije, staračka demencija i demencija kod općih medicinskih stanja.
8. Spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 3, namijenjen upotrebi u liječenju bolesti ili poremećaja kojeg se bira između kognitivnih poremećaja, Alzheimerove bolesti, shizofrenije, boli ili poremećaja spavanja.
9. Kombinacija koja sadrži spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 3, s jednim ili više terapijskih sredstava koja se bira između inhibitora acetilkolinesteraze i antagonista NMDA receptora.
10. Kombinacija u skladu s patentnim zahtjevom 9, pri čemu se inhibitor acetilkolinesteraze bira iz skupine koju čine donepezil, rivastigmin, takrin i galantamin, ili njegova farmaceutski prihvatljiva sol.
11. Kombinacija u skladu s patentnim zahtjevom 9, pri čemu je antagonist NMDA receptora memantin, ili njegova farmaceutski prihvatljiva sol.
12. Kombinacija u skladu s bilo kojim od patentnih zahtjeva 9 do 11, namijenjena upotrebi u liječenju kognitivnih poremećaja, Alzheimerove bolesti, shizofrenije, boli ili poremećaja spavanja kod pacijenta.
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