HRP20170646T1 - Amidi oksalne kiseline kao inhibitori neprilisina, farmaceutski pripravak istog i njihova priprava - Google Patents

Amidi oksalne kiseline kao inhibitori neprilisina, farmaceutski pripravak istog i njihova priprava Download PDF

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HRP20170646T1
HRP20170646T1 HRP20170646TT HRP20170646T HRP20170646T1 HR P20170646 T1 HRP20170646 T1 HR P20170646T1 HR P20170646T T HRP20170646T T HR P20170646TT HR P20170646 T HRP20170646 T HR P20170646T HR P20170646 T1 HRP20170646 T1 HR P20170646T1
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compound according
alkyl
chloro
6alkylene
fluoro
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HRP20170646TT
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Adam Hughes
Erik FENSTER
Melissa Fleury
Roland Gendron
Edmund J. Moran
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Theravance Biopharma R&D Ip, Llc
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Claims (35)

1. Spoj formule I: [image] naznačen time, da: R1 je odabran od H, -C1-8alkila, -C1-3alkilen-C6-10arila, -C1-3alkilen-C1-9heteroarila, -C3-7cikloalkila, -[(CH2)2O],1-3CH3, -C1-6alkilen-OC(O)R10, -C1-6alkilen-NR11R12, -C1-6alkilen-C(O)R13, -C0-6alkilenmorfolinila, -C1-6alkilen- SO2- C1-6alkila, [image] R10 je odabran od -C1-6alkil, -O-C1-6alkila, -C3-7cikloalkila, -O-C3-7cikloalkila, fenila, -O-fenila, -NR11R12, -CH(R15)-NH2, -CH(R15)-NHC(O)O-C1-6alkila i -CH(NH2)CH2COOCH3; a R11 i R12 su neovisno odabrani od H, -C1-6alkila i benzila; ili R11 i R12 su uzeti zajedno kao -(CH2)3-6-, -C(O)-(CH2)3- ili -(CH2)2O(CH2)2-; R13 je odabran od -O-C1-6alkila, -O-benzila i -NR11R12; a R14 je -C1-6alkil ili -C0-6alkilen-C6-10aril; R15 je H3, -CH3, -CH(CH3)2, fenil ili benzil; R2je-OR21 ili-CH2OR21, a R3je H ili-CH3; pri čemu R21 je H, -C(O)-C1-6alkil, -C(O)-CH(R22)-NH2, -C(O)-CH(R22)-NHC(O)O-C1-6alkil ili -P(O)(OR23)2; R22 je H, -CH3, -CH(CH3)2, fenil ili benzil; R23 je H, -C1-6alkil or fenil; ili R2 je uzet zajedno s R1 kako bi se tvorio -OCR15R16- ili -CH2O-CR15R16-, a R3 je odabran od H i -CH3, pri čemu su R15 i R1 neovisno odabrani od H, -C1-6alkila i -O-C3-7cikloalkila, ili R15 i R16 su uzeti zajedno kako bi tvorili =O; ili R2 je uzet zajedno s R3 kako bi tvorio -CH2-O-CH2- ili -CH2-CH2-; ili R2 i R3 su oba -CH3; Z je odabran od -CH- i -N-; R4 je odabran od H, -C1-8alkila, -C1-3alkilen-O-C1-8alkila, -C1-3alkilen-C6-10arila, -C1-3alkilen-O-C6-10arila, -C1-3alkilen-C1-9heteroarila, -C3-7cikloalkila, -[(CH2)2O]1-3CH3, -C1-6alkilen-OC(O)R40, -C1-6alkilen-NR41R42, -C1-6alkilen-C(O)R43, -C0-6alkilenmorfolinila, -C1-6alkilen-SO2-C1-6alkila, [image] R40 je odabran od -C1-6alkila, -O-C1-6alkila, -C3-7cikloalkila, -O-C3-7cikloalkila, fenila, -O-fenila, -NR41R42, -CH(R45)-NH2, -CH(R45)-NHC(O)O-C1.6alkila i -CH(NH2)CH2COOCH3; a R41 i R42 su neovisno odabrani od H, -C1-6alkila i benzila; ili R41 i R42 su uzeti zajedno kao -(CH2)3-6-, -C(OHCH2)3- ili -(CH2)2O(CH2)2-; R43je odabran od -O-C1-6alkila, -O-benzila i -NR41R42; a R44 je -C1-6alkil ili -C0-6alkilen-C6-10aril; R45je H, -CH3, -CH(CH3)2, fenil ili benzil; a je 0 ili 1; R5 je odabran od halo, -CH3, -CF3 i -CN; b je 0 ili cijeli broj od 1 do 3; svaki R6je neovisno odabran od halo, -OH, -CH3, -OCH3, -CN, i-CF3; pri čemu je svaka alkilna skupina u R1 i R4 po izboru supstituirana s 1 do 8 atoma fluora; i pri čemu je metilenski linker na bifenilu po izboru supstituiran s jednom ili dvije -C1-6alkilne skupine ili s ciklopropilom; ili farmaceutski prihvatljiva sol istog.
2. Spoj prema patentnom zahtjevu 1, naznačen time, da R1 je H.
3. Spoj prema patentnom zahtjevu 1, naznačen time, da R1 je odabran od –C1-8alkila, -C1-3alkilen-C6-10arila, -C1-3alkilen-C1-9heteroarila, -C3-7cikloalkila, -[(CH2)2O]1-3CH3, -C1-6alkilen-OC(O)R10, -C1-6alkilen-NR11R12, -C1-6alkilen-C(O)R13, -C0-6alkilenmorfolinila, -C1-6alkilen-SO2-C1-6alkila, [image] ili R1 je uzet zajedno s R2 kako bi tvorio -OCR15R16- ili -CH2O-CR15R16-.
4. Spoj prema patentnom zahtjevu 1, naznačen time, da R1 je odabran od H, -C1-8alkila, -C1-6alkilen-OC(O)R10 i [image] pri čemu R10 je -C1-6alkil, -O-C1-6alkil ili -CH[R15]-NHC(O)O-C1-6alkil; R14 je -C1-6alkil; R15 je -CH(CH3)2; i svaka alkilna skupina u R1 je po izboru supstituirana s 1 do 8 atoma fluora.
5. Spoj prema patentnom zahtjevu 4, naznačen time, da R1 je odabran od H, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -(CH2)3CH3, -(CH2)6CH3,-CH2CF3, -(CH2)2CF3, -CH2CF2CH3, -CH2CF2CF3, -CH2OC(O)CH3, -CH2OC(O) CH2CH3, -CH2OC(O)(CH2)2CH3, -CH2OC(O)OCH2CH3, -CH2OC(O)-CH[CH(CH3)2]-NHC(O)O-CH3 [image] pri čemu R14 je -CH3.
6. Spoj prema bilo kojem od patentnih zahtjeva 1 do 5, naznačen time, da R2 je -OR21, R3 je H i R21 je H; ili R22 je -OR21, R3 je -CH3 i R21 je H; ili R2 je -CH2OR21, R3 je H i R21 je H; ili R2 je -CH2OR21, R3 je -CH3 i R21 je H.
7. Spoj prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time, da R4je H.
8. Spoj prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time, da R4 je odabran od -C1-8alkila, -C1-3alkilen-O-C1-8alkila, -C1-3alkilen-C6-10arila, -C1-3alkilen-O-C1-6arila, -C1-6alkilen-C1-3heteroarila, -C3-7ciklo alkila, -[(CH2)2O]1-3CH3, -C1-6alkilen-OC(O)R40, -C1-6alkilen-NR41R42, -C1-6alkilen-C(O)R43, -C0-6alkilen morfolinila, -C1-6alkilen-SO2-C1-6alkila, [image]
9. Spoj prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time, da R4 je odabran od H, -C1-8alkila, -C1-3alkilen-O-C6-10alkila, -C-1-3alkilen-O-C6-10arila, -[(CH2)2O]1-3CH3 i [image] pri čemu R44 je -C1-6alkil; i svaka alkilna skupina u R4 je po izboru supstituirana s 1 do 8 atoma fluora.
10. Spoj prema patentnom zahtjevu 9, naznačen time, da R4 je odabran od H, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -(CH2)2CF3, -CH2CF2CH3, -(CH2)3-O-CH2CH3, -(CH2)2-O-fenil, -(CH2)2OCH3 i [image] pri čemu R44 je -CH3.
11. Spoj prema bilo kojem od patentnih zahtjeva 1 do 10, naznačen time, da a je 0 ili a je 1 i R5 je halo.
12. Spoj prema patentnim zahtjevima 1 do 11, naznačen time, da b je 0 ili b je 1 i R6 je halo ili b je 2 i svaki R je neovisno odabran od halo i -CH3.
13. Spoj prema patentnom zahtjevom 1, naznačen time, da: a je 0 i b je 0; ili a je 0, b je 1 i R6 je 2'-fluoro, 3'-fluoro, 3'-kloro ili 4'-flouro; ili a je 0, bje 2 i R6je 2'-fluoro, 5'-kloro ili 2'-metil, 5'-kloro ili 2',5'-dikloro; ili a je 1, R je 3-kloro i b je 0; ili a je 1, R5 je 3-kloro, b je 1 i R6 je 3'-kloro; ili a je 1, R5 je 3-kloro, b je 2 i R6 je 2'-fluoro, 5'-kloro.
14. Spoj prema patentnom zahtjevu 6, naznačen time, da R2 je -OR21, R3je H i R21 je H; R1 je odabran od H, -C1-8alkila, -C1-6alkilen-OC(O)R10 [image] i pri čemu R10je -C1-6alkil, -O-C1-6alkil ili -CH[Rl5]-NHC(O)O-C1-6alkil; R14 je -C1-6alkil; R15je -CH(CH3)2; i svaka alkilna skupina u R1 je po izboru supstituirana s 1 do 8 atoma fluora; Z je odabran od -CH- i -N-; R4 je odabran od H, -C1-8alkila, -C1-3alkilen-O-C1-8alkila, -C1-3alkilen-O-C6-10arila, -[(CH2)20]1-3CH3 i [image] pri čemu R44 je -C1-6alkil; i svaka alkilna skupina u R4 je po izboru supstituirana s 1 do 8 atoma fluora; a je 0 i bje 0; ili a je 0, b je 1 i R6 je halo; ili a je 0, b je 2 i jedan R6 je halo i drugi R6 je halo ili -CH3; ili a je 1, R je halo i b je 0; ili a je 1, R5 je halo, b je 1 i R6 je halo; ili a je 1, R5 je halo, b je 2 i svaki R je halo; i gdje je metilenski linker na bifenilu po izboru supstituiran s dvije -CH3 skupine.
15. Spoj prema patentnom zahtjevu 14, naznačen time, da R1 je odabran od H, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -(CH2)3CH3, -(CH2)6CH3,-CH2CF3, -(CH2)2CF3, -CH2CF2CH3, -CH2CF2CF3, -CH2OC(O)CH3, -CH2OC (O) CH2CH3, -CH2OC(O)(CH2)2CH3, -CH2OC(O)OCH2CH3, -CH2OC(O)-CH[CH(CH3)2]-NHC(O)O-CH3 i [image] pri čemu R14 je -CH3; R4 je odabran od H, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -(CH2)2CF3, -CH2CF2CH3, -(CH2)3-O-CH2CH3, -(CH2)2-O-fenil, -(CH2)2OCH3 i [image] pri čemu R44 je -CH3; i a je 0 i b je 0; ili a je 0, b je 1 i R6 je 2'-fluoro, 3'-fluoro, 3'-kloro ili 4'-flouro; ili a je 0, b je 2 i R6 je 2'-fluoro, 5'-kloro ili 2'-metil, 5'-kloro ili 2',5'-dikloro; ili a je 1, R5 je 3-kloro i b je 0; ili a je 1, R5 je 3-kloro, b je 1 i R6je 3'-kloro; ili a je 1, R5 je 3-kloro, b je 2 i R6 je 2'-fluoro, 5'-kloro.
16. Spoj prema patentnom zahtjevu 6, naznačen time, da R2 je -OR21, R3 je -CH3 i R21 je H; R1 je H ili -Ci.8alkil; Z je -N-; R4 je H ili –C1-8alkil; te a i b su 0.
17. Spoj prema patentnom zahtjevu 16, naznačen time, da R1 i R4 jesu H.
18. Spoj prema patentnom zahtjevu 6, naznačen time, da R2 je -CH2OR21, R3 je H i R21 je H; R1 je H ili –C1-8alkil; Z je -CH-; R4 je H ili –C1-8alkil; a je 0 ili a je 1 i R5 je halo; b je 0 ili b je 1 ili 2 i R6 je halo; te gdje je metilenski linker na bifenilu po izboru supstituiran s dvije -CH3 skupine.
19. Spoj prema patentnom zahtjevu 18, naznačen time, da R1 je H, -CH2CH3 ili –(CH2)3CH3; R4 je H; a je 0 ili a je 1 i R5 je 3-kloro; b je 0 ili b je 1 i R6 je 2'-fluoro, 3'-fluoro, 3'-kloro ili 4'-flouro.
20. Spoj prema patentnom zahtjevu 6, naznačen time, da R2 je -CH2OR21, R3je -CH3 i R21 je H; R1 je H ili –C1-8alkil; Z je -CH-; R4 je H ili –C1-8alkil; a je 0; i b je 0 ili b je 1 i R6 je halo.
21. Spoj prema patentnom zahtjevu 20, naznačen time, da R1 je H ili -CH2CH3; R4 je H ili -CH2CH(CH3)2; i b je 0 ili b je 1 i R6 je 2'- fluoro, 3'-fluoro, 3'-kloro ili 4'-flouro.
22. Spoj prema patentnom zahtjevu 1, naznačen time, da R1 je odabran od H, -C1-8alkila, -C1-6alkilen-OC(O)R10i [image] pri čemu R10 je -C1-6alkil, -O-C1-6alkil ili -CH[R15]-NHC(O)O-C1-6alkil; R14 je -C1-6alkil; R15 je -CH(CH3)2; i svaka alkilna skupina u R1 je po izboru supstituirana s 1 do 8 atoma fluora; R4 je odabran od H, -C1-8alkila, -C1-3alkilen-O-C1-8alkila, -C1-3alkilen-0-C6-10arila, -[(CH2)2O]i-3CH3 i [image] pri čemu R44 je -C-1-6alkil; i svaka alkilna skupina u R4 je po izboru supstituirana s 1 do 8 atoma fluora; a je 0 i b je 0; ili a je 0, b je 1 i R6 je 2'-fluoro, 3'-fluoro, 3'-kloro ili 4'-flouro; ili a je 0, b je 2 i R6 je 2'-fluoro, 5'-kloro ili 2'-metil, 5'-kloro ili 2',5'-dikloro; ili a je 1, R5 je 3-kloro i b je 0; ili a je 1, R5 je 3-kloro, b je 1 i R6je 3'-kloro; ili a je 1, R5 je 3-kloro, b je 2 i R6 je 2'-fluoro, 5'-kloro; te gdje je metilenski linker na bifenilu po izboru supstituiran s dvije -CH3 skupine.
23. Spoj prema patentnom zahtjevu 22, naznačen time, da R2 je -OR21 ili -CH2OR2'; i R3 je H ili -CH3; gdje R2' je H.
24. Postupak za pripravu spoja prema bio kojem od patentnih zahtjeva 1 do 23, naznačen time, da se sastoji od koraka spajanja spoja formule 1 sa spojem formule 2: [image] kako bi se dobio spoj formule I; pri čemu su R1-R6, a i b definirani u patentnom zahtjevu 1 i P je odabran od H i amino-zaštitne skupine odabrane od f-butoksikarbonila, tritila, benziloksikarbonila, 9-fluorenilmetoksikarbonila, formila, trimetilsilila i t-butildimetilsilila; te gdje se postupak dalje sastoji od skidanja zaštite spoju formule 1 pri čemu je P zaštitna amino skupina.
25. Farmaceutski pripravak koji sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 23 i farmaceutski prihvatljivi nosač, naznačen time, da po izboru nadalje sadrži terapijsko sredstvo odabrano od antagonista receptora adenozina, antagonista a-adrenergičkog receptora, antagonista (31-adrenergičkog receptora, agonista β2-adrenergičkog receptora, agonista dvostrukog djelovanja (3-adrenergičkog receptora/a1-receptor antagonista, prekidača krajnjeg prozvoda poboljšane glikozilacije, antagonista aldosterona, inhbitora sintaze aldosterona, inhibitora N aminopeptidaze, androgena, inhibotira enzima za pretvaranje angiotensina i enzima za pretvaranje angiotensina s dvostrukim djelovanjem/inbibitora neprilisina, aktivatore enzima 2 za pretvaranje angiotensina i stimulatore, angiotensin-ll cjepiva, antikoagulanse, anti-diabetička sredstva, sredstva protiv proljeva, sredstva protiv glaukoma, anti-lipidna sredstva, antinociceptivna sredstva, anti-trombotička sredstva, ATi receptor antagoniste i ATi receptor antagoniste s dvostrukim djelovanjem/neprilisin inhibitore i multifunkcionalne blokatore angiotensin receptora, antagoniste receptora bradikinina, blokatore kalcijevih kanala, inhibitore kimaze, digoksin, diuretike, agoniste dopamina, inhibitore enzima za pretvaranje endotelina, antagoniste receptora endotelina, inhibitore HMG-CoA reduktaze, estrogene, agoniste i/ili antagoniste receptora estrogena, inhibitore monoaminske reapsorpcije, sredstva za relaksaciju mišića, natriuretske peptide i njihove analoge, antagoniste receptora natriuretskog klirens peptida, inhibitore neprilisina, donore dušikovog oksida, ne-steroidna protuupalna sredstva, antagoniste receptora N-metil d-aspartata, agoniste receptora opioida, inhibitore fosfodiesteraze, analoge prostaglandina, agoniste receptora prostaglandina, inhibitore renina, inhibitore selektivne reapsorpcije serotonina, blokatore natrijevih kanala, topljive stimulatore i aktivatore gvanilat ciklaze, triciklička sredstva protiv depresije, antagoniste receptora vazopresina i kombinacije istih.
26. Farmaceutski pripravak prema patentnom zahtjevu 25, naznačen time, da je terapijsko sredstvo antagonist receptora AT1.
27. Spoj prema bilo kojem od patentnih zahtjeva 1 do 23, naznačen time, da se koristi u terapiji.
28. Spoj prema patentnom zahtjevu 27, naznačen time, da je za uporabu u liječenju povišenog krvnog tlaka, srčanog zatajenja ili bolesti bubrega.
29. Spoj prema patentnom zahtjevu 1, naznačen time, da spoj ima formulu: [image] ili farmaceutski prihvatljivu sol istog.
30. Spoj prema patentnom zahtjevu 29, naznačen time, da R1 je H.
31. Spoj prema patentnom zahtjevu 29, naznačen time, da R4 je -C1-8alkil.
32. Spoj prema patentnom zahtjevu 29, naznačen time, da R21 je H.
33. Spoj prema patentnom zahtjevu 29, naznačen time, da Z je -CH-.
34. Spoj prema patentnom zahtjevu 29, naznačen time, da a je 0.
35. Spoj prema patentnom zahtjevu 1, naznačen time, da je spoj (2S,4R)-5-(5'-kloro2'-fluorobifenil-4-il) -2-hidroksimetil-2- metil-4-(oksalilamino)pentanoična kiselina ili farmaceutski prihvatljiva sol istog.
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