HRP20201473T1 - Inhibitori lizin gingipaina - Google Patents

Inhibitori lizin gingipaina Download PDF

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Publication number
HRP20201473T1
HRP20201473T1 HRP20201473TT HRP20201473T HRP20201473T1 HR P20201473 T1 HRP20201473 T1 HR P20201473T1 HR P20201473T T HRP20201473T T HR P20201473TT HR P20201473 T HRP20201473 T HR P20201473T HR P20201473 T1 HRP20201473 T1 HR P20201473T1
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Croatia
Prior art keywords
group
compound
hydrogen
pharmaceutically acceptable
nrd
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HRP20201473TT
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English (en)
Inventor
Andrei Konradi
Stephen S. Dominy
Casey Crawford Lynch
Craig Coburn
Joseph Vacca
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Cortexyme, Inc.
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Publication of HRP20201473T1 publication Critical patent/HRP20201473T1/hr

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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Claims (15)

1. Spoj prema formuli I: [image] ili njegova farmaceutski prihvatljiva sol, naznačen time, što Z je ariloksimetil-karbonil sa supstituiranim halogenom; A je odabran iz grupe koja se sastoji od -CH2- i -O-; B i D su zasebno odabrani iz grupe koja se sastoji od vodika, halogena, C1-4 haloalkila i C1-4 haloalkoksija; R1 je odabran iz grupe koja se sastoji od vodika i zaštitne grupe za amine, naznačeno time, što je zaštitna grupa za amine odabrana iz grupe koja se sastoji od benziloksikarbonila, 9-fluorenilmetiloksikarbonila, terc-butiloksikarbonila, aliloksikarbonila, acetamido i ftalimido; R2 je vodik; i R3 je odabran iz grupe koja se sastoji od C6-10 arila, heteroarila s 5 do 12 članova, C1-8 alkila, C3-8 cikloalkila, zasićenog heterociklila s 5 do 12 članova, -L-R5 i -OR6, naznačeno time, što L je odabran iz grupe koja se sastoji od -O-, -NR-, C1-4 alkilena i heteroalkilena s 2 do 4 člana, naznačeno time, što je R odabran iz grupe koja se sastoji od vodika i C1-8 alkila, R5 je odabran iz grupe koja se sastoji od C6-10 arila, heteroarila s 5 do 12 članova, C3-8 cikloalkila i zasićenog heterociklila s 5 do 12 članova, i -OR6 i karbonil s kojim je spojen formiraju zaštitnu grupu za amine, naznačeno time, što je zaštitna grupa za amine odabrana iz grupe koja se sastoji od benziloksikarbonila, 9-fluorenilmetiloksikarbonila, terc-butiloksikarbonila i aliloksikarbonila, i naznačeno time, što je R3 opcionalno supstituiran s jednim ili više supstituenata odabranih iz grupe koja se sastoji od halo, -CN, -NO2, -N3, -OH, Ra, Rb, -ORa, -ORb, -(CH2)kC(O)Rc, -NRd(CH2)uC(O)Rc, -O(CH2)uC(O)Rc, -(CH2)kCONRdRd, -(CH2)kNRdC(O)Rc, -NRd(CH2)uCONRdRd, -NRd(CH2)uNRdC(O)Rc, -O(CH2)uCONRdRd, -O(CH2)uNRdC(O)Rc, -(CH2)kS(O)2NRdRd, -(CH2)kNRdS(O)2Rc, -(CH2)kS(O)2Rc, -(CH2)kS(O)Rc, -(CH2)kSRd, -NRd(CH2)uS(O)2NRdRd, -NRd(CH2)uNRdS(O)2Rc, -NRd(CH2)uS(O)2Rc, -NRd(CH2)uS(O)Rc, -NRd(CH2)uSRd, -O(CH2)uS(O)2NRdRd, -O(CH2)uNRdS(O)2Rc, -O(CH2)uS(O)2Rc, -O(CH2)uS(O)Rc i -O(CH2)uSRc, naznačeno time, što: svaki Ra je zasebno odabran iz grupe koja se sastoji od C1-4 alkila i C1-4 haloalkila, svaki Rb je zasebno odabran iz grupe koja se sastoji od C3-6 cikloalkila, C3-6 halocikloalkila, C6-10 arila, heteroarila s 5 do 12 članova i zasićenog heterociklila s 5 do 12 članova, svaki Rc je zasebno odabran iz grupe koja se sastoji od -OH, C1-8 alkila, C1-8 haloalkila, C3-8 cikloalkila, C3-8 halocikloalkila, C6-10 arila, (C6-10 arila)-(C1-8 alkila), heteroarila s 5 do 12 članova i zasićenog heterociklila s 5 do 12 članova, svaki Rd je zasebno odabran iz grupe koja se sastoji od vodika i C1-8 alkila, svaki k u indeksu je zasebno odabran iz 0, 1, 2, 3, 4, 5 i 6; i svaki u u eksponentu je zasebno odabran iz 1, 2, 3, 4, 5 i 6; i R4 je odabran iz grupe koja se sastoji od vodika, halogena, C1-4 alkila, C1-4 alkoksi, C1-4 haloalkila i C1-4 haloalkoksija; pod uvjetom da kada je Z supstituiran fenoksimetil-karbonilom, A je -CH2-, a B i D su vodik, onda R3 nije (2-fenil)etil ili supstituirani (2-fenil)etil.
2. Spoj prema patentnom zahtjevu 1, koji ima strukturu prema formuli Ib: [image] ili njegova farmaceutski prihvatljiva sol, naznačen time, što B i D su zasebno odabrani iz grupe koja se sastoji od vodika, halogena, halometila i halometoksija.
3. Spoj prema patentnom zahtjevu 1 ili 2, naznačen time, što je R3 odabran iz grupe koja se sastoji od C6-10 arila, heteroarila s 5 do 12 članova, C3-8 cikloalkila, zasićenog heterociklila s 5 do 12 članova i -L-R5.
4. Spoj prema patentnom zahtjevu 2 ili njegova farmaceutski prihvatljiva sol, sa strukturom prema formuli Id: [image] ili njegova farmaceutski prihvatljiva sol, naznačen time, što je R3 odabran iz grupe koja se sastoji od C6-10 arila, heteroarila s 5 do 12 članova, C3-8 cikloalkila, zasićenog heterociklila s 5 do 12 članova i -L-R5, naznačeno time, što je L C1-4 alkilen.
5. Spoj prema patentnom zahtjevu 1, naznačen time, što je spoj formule I odabran iz grupe koja se sastoji od: [image] [image]
6. Spoj prema patentnom zahtjevu 4 ili njegova farmaceutski prihvatljiva sol, naznačen time, što R3 je odabran iz grupe koja se sastoji od cikloheksila, ciklopentila, morfolino, fenila, piperidinila, piridinila, tetrahidrofuranila, tetrahidropiranila, 1,2,3,4-tetrahidronaftila i tiazolila, pri čemu je svaki opcionalno supstituiran s 1 do 3 člana odabrana iz grupe koja se sastoji od metila, metoksija, trifluorometila, acetila i -N3.
7. Spoj koji ima strukturu prema formuli Ib: [image] ili njegova farmaceutski prihvatljiva sol, naznačen time, što A je odabran iz grupe koja se sastoji od -CH2- i -O-; B i D su zasebno odabrani iz grupe koja se sastoji od vodika, halogena, halometila i halometoksija R1 je odabran iz grupe koja se sastoji od vodika i zaštitne grupe za amine, naznačeno time, što je zaštitna grupa za amine odabrana iz grupe koja se sastoji od benziloksikarbonila, 9-fluorenilmetiloksikarbonila, terc-butiloksikarbonila, aliloksikarbonila, acetamido i ftalimido; R2 je vodik; Z je odabran iz grupe koja se sastoji od piridin-2-il-karbonila i tiazol-2-il-karbonila, i R3 je odabran iz grupe koja se sastoji od C6-10 arila i C3-8 cikloalkila; ili spoj odabran iz grupe koja se sastoji od: [image] i njegove farmaceutski prihvatljive soli.
8. Spoj prema patentnom zahtjevu 1 ili njegova farmaceutski prihvatljiva sol, naznačen time, što je R4 odabran iz grupe koja se sastoji od C1-4 alkila i C1-4 haloalkila, opcionalno naznačen time, što je spoj [image] ili njegova farmaceutski prihvatljiva sol.
9. Farmaceutski pripravak koji obuhvaća spoj prema bilo kojem patentnom zahtjevu od 1 do 8 i farmaceutski prihvatljiv ekscipijens.
10. Spoj prema bilo kojem patentnom zahtjevu od 1 do 8 za primjenu u liječenju infekcije bakterijom P. gingivalis.
11. Spoj prema bilo kojem patentnom zahtjevu od 1 do 8 za primjenu u liječenju poremećaja mozga povezanog s infekcijom bakterijom P. gingivalis.
12. Spoj za primjenu prema patentnom zahtjevu 11, naznačen time, što je poremećaj mozga odabran iz grupe koja se sastoji od Alzheimerove bolesti, Downovog sindroma, epilepsije, autizma, Parkinsonove bolesti, esencijalnog tremora, frontotemporalne demencije, progresivne supranuklearne paralize, amiotrofične lateralne skleroze, Huntingtonove bolesti, multiple skleroze, blagog kognitivnog oštećenja, oštećenja pamćenja povezanog sa starenjem, kronične traumatske encefalopatije, moždanog udara, demencije Lewyevih tjelešaca, multiple sistemske atrofije, shizofrenije i depresije.
13. Spoj za primjenu prema patentnom zahtjevu 12, naznačen time, što je poremećaj mozga Alzheimerova bolest i naznačen time, što liječenje dodatno uključuje primjenu u subjekta jedne ili više djelatnih tvari odabranih iz grupe koja se sastoji od inhibitora kolinesteraze, serotoninskog modulatora, modulatora NMDA, terapije usmjerene na Aβ, terapije usmjerene na ApoE, terapije usmjerene na mikrogliju, terapije usmjerene na krvno-moždanu barijeru, terapije usmjerene na tau, terapije usmjerene na komplement i protuupalne terapije.
14. Spoj za primjenu prema bilo kojem patentnom zahtjevu od 10 do 13, naznačen time, što se spoj primjenjuje u subjekt u trajanju od: (a) najmanje mjesec dana; (b) najmanje godinu dana; ili (c) najmanje 10 godina.
15. Spoj za primjenu prema bilo kojem patentnom zahtjevu od 10 do 14, naznačen time, što je subjekt čovjek, pas ili mačka.
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