HRP20190624T1 - Pozitivni alosterni modulatori muskarinskog m1 receptora - Google Patents

Pozitivni alosterni modulatori muskarinskog m1 receptora Download PDF

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HRP20190624T1
HRP20190624T1 HRP20190624TT HRP20190624T HRP20190624T1 HR P20190624 T1 HRP20190624 T1 HR P20190624T1 HR P20190624T T HRP20190624T T HR P20190624TT HR P20190624 T HRP20190624 T HR P20190624T HR P20190624 T1 HRP20190624 T1 HR P20190624T1
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carboxamide
benzo
oxazine
hydroxycyclohexyl
cis
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HRP20190624TT
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Ramakrishna Nirogi
Abdul Rasheed Mohammed
Anil Karbhari Shinde
Shankar Reddy GAGGINAPALLY
Venkateswarlu Jasti
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Suven Life Sciences Limited
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

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  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Claims (12)

1. Spoj formule (I), pri čemu: A1i A2svaki neovisno predstavlja CH, CF ili N; W je O, S, S(O) ili S(O)2; R1je R2je pri čemu * predstavlja točku vezivanja; R3je OH, F, NH2ili H; R4je pri svakoj pojavi neovisno odabran od halogena, -O-CH3; -S-CH3, -N(CH3)2, -CH3, -CF3, -CHF2, -CH2F, -OH, -CN, fenila, piridila i vodika; pri čemu su fenil i piridil izborno supstituirani s jednim ili više supstituenata odabranih iz skupine sastavljene od halogena ili CH3; X je CH2, O ili NH; a je 0 ili 1; i b je 1 ili 2; ili izotopski oblik, stereoizomer, tautomer ili njegova farmaceutski prihvatljiva sol.
2. Spoj formule (I) sukladno zahtjevu 1, pri čemu: W je O; A1i A2 su CH; R1je R2je
3. Spoj formule (I) sukladno zahtjevu 1, pri čemu: W je S; A1i A2su CH; R1je R2je
4. Spoj formule (I) sukladno zahtjevu 1, pri čemu: W je O; A1i A2su CH; R1je R2je i X je CH2.
5. Spoj formule (I) sukladno zahtjevu 1, pri čemu: W je S; A1i A2su CH; R1je R2je i X je CH2.
6. Spoj sukladno bilo kojem od zahtjeva 1 do 5, pri čemu je spoj odabran iz skupine sastavljene iz slijedećih: N-(cis-1S,2S-2-hidroksicikloheksil)-4-(2-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-8-fluoro-4-(2-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-{2-fluorobenzil}-4H-pirido[3,2-b][1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-benzil-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(4-metoksibenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(2-hidroksi-2-metilpropil)-4-(4-metoksibenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(3-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(2-hidroksi-2-metilpropil)-4-(3-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(3-metoksibenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(2-hidroksi-2-metilpropil)-4-(3-metoksibenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(2-metoksipiridin-4-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(2-hidroksi-2-metilpropil)-4-(2-metoksipiridin-4-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(4-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(2-hidroksi-2-metilpropil)-4-(4-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(2-metoksipiridin-5-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(2-hidroksi-2-metilpropil)-4-(2-metoksipiridin-5-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(3-trifluorometilbenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(2,3-difluoro benzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(3,4-difluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(3-hidroksitetrahidropiran-4-il)-4-(2,3-difluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(2-hloropiridin-5-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(piridin-3-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(piridin-4-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(2-hloropiridin-4-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(piridin-2-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(3,4-dihloro benzil)-4H-benzo [1,4] oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(2-metilpiridin-3-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(2,4-dihlorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-8-fluoro-4-(2,3-difluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-benzil-4H-pirido[3,2-b][1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-1-benzil-1H-pirido[2,3-b][1,4]oksazin-3-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-1-{2,3-difluorobenzil}-1H-pirido[2,3-b][1,4]oksazin-3-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(2,3-difluorobenzil)-4H-pirido[3,2-b][1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(3-fluoropiridin-4-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(4-fluorobenzil)-4H-pirido[3,2-b][1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-1-(3-fluorobenzil)-1H-pirido[2,3-b][1,4]oksazin-3-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(2-trifluorometilbenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(2-hlorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(trans-1R,2R-2-hidroksiciklopentil)-4-(2,3-difluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(trans-1R,2R-2-hidroksiciklopentil)-4-(2-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(2-hlorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(trans-1R,2R-2-hidroksiciklopentil)-4-(2,3-difluorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(2-hidroksimetilfenil)-4-(2-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(2-hidroksimetilfenil)-4-(2,3-difluorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(2-hidroksimetilfenil)-4-(2,3-difluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(2-hidroksimetilfenil)-4-(2-fluorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(1-hidroksimetil-2-metilpropil)-8-fluoro-4-(2-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-benzil-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1R,2R-2-hidroksicikloheksil)-4-{2-fluorobenzil}-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1R,2R-2-hidroksicikloheksil)-4-{2-fluorobenzil}-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-{3-fluorobenzil}-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(2-fenilpiridin-4-ilmetil)-4H-benzo[1,4] oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-8-fluoro-4-(2-fenilpiridin-4-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(2-hloropiridin-4-ilmetil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(2-fluorobenzil)-5-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(piridin-2-ilmetil)-5-fluoro-4H-benzo[1,4] oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(piridin-4-ilmetil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(6’-fluoro-5’-metil-[2,3’]bipiridinil-4-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-[2-(1-metil-1H-pirazol-3-il)-piridin-4-ilmetil]-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(1-metil-1H-pirazol-3-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(2-fluorobenzil)-5,8-difluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-8-fluoro-4-(3-fluoropiridin-4-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-8-fluoro-4-(2-metilpiridin-4-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-8-fluoro-4-(2-metilpiridin-5-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(2-metilpiridin-4-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(2-metilpiridin-5-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-5,8-difluoro-4-(piridin-4-ilmetil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(3-hidroksitetrahidropiran-4-il)-4-(3-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(3-hidroksitetrahidropiran-4-il)-4-(4-fluorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(3-hidroksitetrahidropiran-4-il)-4-(3-trifluorometilbenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(3-hidroksitetrahidropiran-4-il)-4-(2-metoksipiridin-5-ilmetil)-4H-benzo[l,4]oksazin-2-karboksamid; N-(3-hidroksitetrahidropiran-4-il)-4-(piridin-4-ilmetil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(3-fluoropiperidin-4-il)-4-(2-fluorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(3-fluoropiperidin-4-il)-4-(2,3-difluorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(3-hidroksipiperidin-4-il)-4-(2,3-difluorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid; N-(3-hidroksipiperidin-4-il)-4-(2-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(2,3-difluorobenzil)-4H-benzo[1,4]tiazin-2-karboksamid; N-(cis-1S, 2S-2-hidroksicikloheksil)-4-(3-fluorobenzil)-4H-benzo[1,4]tiazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-benzil-4H-benzo[1,4]tiazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-{4-metoksibenzil}-4H-benzo[1,4]tiazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-{4-fluorobenzil}-4H-benzo[1,4]tiazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-{piridin-4-il-metil}-4H-benzo[1,4]tiazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-{2-hloropiridin-5-il-metil}-4H-benzo[1,4]tiazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-{piridin-2-il-metil}-4H-benzo[1,4]tiazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-(2,3-difluorobenzil)-1-okso-4H-benzo[1,4]tiazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-benzil-1-okso-4H-benzo[1,4]tiazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-{3-fluorobenzil}-1-okso-4H-benzo[1,4]tiazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-{piridin-2-il-metil}-1-okso-4H-benzo[1,4]tiazin-2-karboksamid; N-(cis-1S,2S-2-hidroksicikloheksil)-4-{2-hloropiridin-5-il-metil}-1-okso-4H-benzo[1,4]tiazin-2-karboksamid; N-(3-hidroksipiperidin-4-il)-4-(4-fluorobenzil)-8-fluoro-4H-benzo[1,4] oksazin-2-karboksamid; N-(3-hidroksipiperidin-4-il)-4-(4-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid; N-(3-hidroksipiperidin-4-il)-4-(2,3-difluorobenzil)-4H-benzo[1,4] oksazin-2-karboksamid; i N-(3-hidroksipiperidin-4-il)-4-(2-fluorobenzil)-8-fluoro-4H-benzo[1,4] oksazin-2-karboksamid; ili njegove farmaceutski prihvatljive soli.
7. Spoj sukladno bilo kojem od zahtjeva 1 do 6, pri čemu je farmaceutski prihvatljiva sol odabrana iz skupine sastavljene iz slijedećih: N-(3-fluoropiperidin-4-il)-4-(2-fluorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid hidrohlorid; N-(3-fluoropiperidin-4-il)-4-(2,3-difluorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid hidrohlorid; N-(3-hidroksipiperidin-4-il)-4-(2,3-difluorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid trifluoroacetat; N-(3-hidroksipiperidin-4-il)-4-(2-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid trifluoroacetat; N-(3-hidroksipiperidin-4-il)-4-(4-fluorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid trifluoroacetat; N-(3-hidroksipiperidin-4-il)-4-(4-fluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid trifluoroacetat; N-(3-hidroksipiperidin-4-il)-4-(2,3-difluorobenzil)-4H-benzo[1,4]oksazin-2-karboksamid trifluoroacetat; i N-(3-hidroksipiperidin-4-il)-4-(2-fluorobenzil)-8-fluoro-4H-benzo[1,4]oksazin-2-karboksamid trifluoroacetat.
8. Farmaceutski pripravak sukladno bilo kojem od zahtjeva 1 do 7, i farmaceutski prihvatljive ekscipijense ili nosače.
9. Farmaceutski pripravak sukladno zahtjevu 8, radi liječenju kliničkih stanja uzrokovanih muskarinskim M1 receptorom odabranih iz skupine sastavljene od Alzheimerove bolesti, Shizofrenije, kognitivnih poremećaja, boli ili poremećaja spavanja.
10. Spoj sukladno bilo kojem od zahtjeva 1 do 7, radi liječenju kliničkih stanja uzrokovanih muskarinskim M1 receptorom odabranih iz skupine sastavljene od Alzheimerove bolesti, Shizofrenije, kognitivnih poremećaja, boli ili poremećaja spavanja.
11. Spoj sukladno bilo kojem od zahtjeva 1 do 7, radi liječenju poremećaja povezanog sa muskarinskim M1 receptorom.
12. Spoj radi primjene sukladno zahtjevu 11, pri čemu je poremećaj povezan s muskarinskim M1 receptorom odabranih iz skupine sastavljene od Alzheimerove bolesti, Shizofrenije, kognitivnih poremećaja, boli ili poremećaja spavanja.
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