HRP20171097T1 - Inhibitori neprilizina - Google Patents

Inhibitori neprilizina Download PDF

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HRP20171097T1
HRP20171097T1 HRP20171097TT HRP20171097T HRP20171097T1 HR P20171097 T1 HRP20171097 T1 HR P20171097T1 HR P20171097T T HRP20171097T T HR P20171097TT HR P20171097 T HRP20171097 T HR P20171097T HR P20171097 T1 HRP20171097 T1 HR P20171097T1
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Croatia
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compound according
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6alkyl
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HRP20171097TT
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Erik FENSTER
Melissa Fleury
Adam D. Hughes
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Theravance Biopharma R&D Ip, Llc
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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Claims (32)

1. Spoj formule I: [image] naznačen time, da : R1 je odabran iz skupine koju tvore H; C1-8alkil po želji supstituiran s jednim ili više fluoro atoma; C1-3alkilen-C6-10aril; C1-3alkilen-C1-9eteroaril; C3-7cikloalkil; C2-3alkilen-OH; -[(CH2)2O]1-3CH3; C1-6alkilen-OC(C)R20; C1-6alkilen-NR21R22; -CH2CH(NH2)-COOCH3; C1-6alkilen-C(O)R23; C0-6alkilenmorfolin; C1-6alkilen-SO2-C1-6alkil; [image] pri čemu je R20 odabran iz skupine koju tvore C1-6alkil, -O-C1-6alkil, C3-7cikloalkil, -O-C3-7cikloalkil, fenil, -O-fenil, -NR21R22, -CH(R25)-NH2, -CH(R25)-NHC(O)O-C1-6alkil, i -CH(NH2)CH2COOCH3; i R21 i R22 neovisno su odabrani iz skupine koju tvore H, C1-6alkil, i benzil; ili R21 i R22 zajedno tvore -(CH2)3-6-, -C(O)-(CH2)3-, ili -(CH2)2O(CH2)2-; R23 je odabran iz skupine koju tvore -O-C1-6alkil, -O-benzil, i - NR21R22; R24 je C1-6alkil ili C0-6alkilen-C6-10 aril; i R25 je H, -CH3, -CH(CH3)2, fenil, ili benzil; R2 je -OH, -CH2OH, ili -CH2-O-C1-6alkil; i R3 je H ili -CH3; R4 i R5 neovisno su odabrani iz skupine koju tvore vodik, halo, -OH, -CH3, -OCH3, -CN, and -CF3; X je H, -C(O)-R6, -C(O)-NR7R8, -C(O)-NR9-NR10R11, -C(O)-NR12-NR13-C(O)-R14, ili -CH(R15)-OR16; R6 je C1-6alkil, C1-6alkil -O- C1-6alkil, C6-10aril, benzil, ili C1-9heteroaril; R7 je H, -OH, ili C1-6alkil; R8 je C1-6alkil; -O- C1-6alkil; C5-6cikloalkil; C6-10aril; -O-C6-10aril; -O-benzil; piridin po želji supstituiran s halo, -OH, C1-6alkil, ili -O- C1-6alkil; morfolin; ili izoksazolidinon; ili R7 i R8 zajedno tvore prsten odabran iz skupine koju tvore: [image] [image] i pri čemu je a 1 i R26 je -OH, ili je a 2 i svaki R26 neovisno je odabran od halo ili -C1-3alkilen-OH; R27 je –C1-3alkilen-OH, -C(O)NH2, ili -SO2CH3; b je 0, ili b je 1 i R28 je –C1-3alkilen-OH, ili b je 2 i svaki R28 je C1-6alkil; R29 je halo, -COOH, -OH, -C1-3alkilen-OH, -CH2O-CH3, -CONH2, -CN, ili piridin; R30 je C1-6alkil ili C3-7cikloalkil; R31 je -OH ili -C1-3alkilen-OH; R32 je halo; C1-6alkil; C2-4alkilen-O- C1-6alkil; -C(O)OC1-6alkil; -C(O)N(CH3)2; piridin; -SO2CH3; -C(O)-furan; ili je fenil supstituiran s halo, -O- C1-6alkil, ili -CN; i R33 je H, -OH, -O- C1-6alkil ili -O-C6-10aril; R9 je H ili C1-6alkil; R10 je H ili C1-6alkil; R11 je C1-6alkil; C1-9heteroaril po želji supstituiran s halo, -OH, C1-6alkil, ili -O- C1-6alkil; dihidroimidazol; ili fenil po želji supstituiran s jednom ili više skupina odabranih od halo, C1-6alkil, -O- C1-6alkil, i -NO2; R12 je H ili C1-6alkil; R13 je H ili C1-6alkil; R14 je -O-benzil; piridin po želji supstituiran s halo, -OH, C1-6alkil, ili -O- C1-6alkil; furan; ili fenil supstituiran s halo, -OH, -O-C1-6alkil, ili -NO2; R15 H ili C1-6alkil; R16 je H, C1-6alkil, -[(CH2)2O]i-3CH3, C1-9heteroaril, benzil, ili C6_10aril po želji supstituiran s –OH ili -OCH3; ili R15 i R16 zajedno tvore -(CH2)4-; ili njegovu farmaceutski prihvatljivu sol .
2. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je R1 je H.
3. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je R1 odabran iz skupine koju tvore C1-8alkil po želji supstituiran s jednim ili više fluoro atoma; C1-3alkilen-C6-10aril; C1-3alkilen-C1-9heteroaril; C3-7cikloalkil; C2-3alkilen-OH;-t(CH2)2O]1-3CH3; C1-6alkil -OC(O)R20; C1-6alkilen -NR21R22; -CH2CH(NH2)-COOCH3; C1-6alkilen-C(O)R23; C0-6alkilenmorfolin; C1-6alkilen -SO2- C1-6alkil; [image]
4. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je R2 -OH i R3 je H.
5. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je R2 -OH i R3 je -CH3.
6. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je R2 -CH2OH i R3 je H.
7. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je R2 -CH2OH i R3 je -CH3.
8. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je R4 vodik ili halo.
9. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je R5 halo.
10. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je X -C(O)-R6 i ima formulu a: [image]
11. Spoj u skladu s patentnim zahtjevom 10 , naznačen time, da je R2 -OH i R3 je H.
12. Spoj u skladu s patentnim zahtjevom 10, naznačen time, da je R5 -CH2CH3, -CH2CH(CH3)2, ili benzil.
13. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je X -C(O)-NR7R8 i ima formulu b: [image]
14. Spoj u skladu s patentnim zahtjevom 13 naznačen time, da je R2 -OH i R3 je H.
15. Spoj u skladu s patentnim zahtjevom 13, naznačen time, da je R7 H, -OH, ili -CH3; i R8 je -CH3, -O-CH3, ciklopentil, fenil, -O-benzil, piridin, piridin supstituiran s halo, piridin supstituiran s C1-6alkilom, morfolinom, ili izoksazolidinonom; ili R7 i R8 zajedno tvore prsten odabran iz skupine koju tvore: [image] pri čemu je a 1 i R26 je -OH, ili je a 2 i svaki R26 je halo; R27 je -CH2-OH, -C(O)NH2, ili -SO2CH3; b je 0, ili b je 1 i R28 je -CH2-OH, ili b je 2 i svaki R28 je -CH3; R29 je fluoro, -COOH, -OH, -CH2OH, -(CH2)2OH, -CH2O-CH3, -CONH2, -CN, ili piridin; R30 je -CH3; R31 je -OH; R32 je -CH3, -(CH2)2OCH2CH3, -C(O)OCH3, -C(O)OCH2CH3, -C(O)N(CH3)2, -SO2CH3, -C(O)-furan, ili je fenil supstituiran s -CN; i R33 je H ili -OH.
16. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je X -C(O)-NR9-NR10R11, i ima formulu c: [image]
17. Spoj u skladu s patentnim zahtjevom 16, naznačen time, da je R2 je -OH i R3 je H.
18. Spoj u skladu s patentnim zahtjevom 16, naznačen time, da je R9 H; R10 je H, a i R11 je odabran između -CH3; -CH2CH(CH3)2; piridina; pirimidina supstituiranog s -OH; dihidroimidazola; i fenila po želji supstituiranog s jednom ili dvije skupine odabrane između Cl, F, Br, -CH3, -OCH3, i -NO2.
19. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je X -C(O)-NR12-NR13-C(O)-R14 i ima formulu d: [image]
20. Spoj u skladu s patentnim zahtjevom 19, naznačen time, da je R2 -OH i R3 je H.
21. Spoj u skladu s patentnim zahtjevom 19, naznačen time, da je R12 H; R13 je H; i R14 je -O-benzil; piridin; piridin supstituiran s halo; furan; ili fenil supstituiran s -OH ili -NO2.
22. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je X je -CH(R15)-OR16 i ima formulu e: [image]
23. Spoj u skladu s patentnim zahtjevom 22, naznačen time, da je R2 -OH i R3 je H ili je R2 -CH2OH i R3 je -CH3.
24. Spoj u skladu s patentnim zahtjevom 22, naznačen time, da je R15 je H; R16 je odabran između H, -CH3, -CH(CH3)2, -CH2CH3, piridin, benzil, fenil, fenil supstituiran s -OH, i fenil supstituiran s -OCH3; ili R15 i R16 zajedno tvore -(CH2)4-.
25. Spoj u skladu s patentnim zahtjevom 1, naznačen time, da je X H i ima formulu f: [image]
26. Spoj u skladu s patentnim zahtjevom 25, naznačen time, da je R2 -CH2OH i R3 je -CH3.
27. Postupak priprave spoja u skladu s bilo kojim patentnim zahtjevom od 1 do 26, naznačen time, da obuhvaća korak spajanja (i) spoja formule 1: [image] sa spojem formule 2 ili formule 7 ili formule 8 ili mravlje kiseline: [image] ili (ii) Spoj formule 3: [image] sa spojem formule 4 ili formule 5 ili formule 6: [image] kako bi se proizveo spoj formule I; pri čemu je P1 H ili karboksi zaštitna skupina odabrana između metila, etila, t-butila, benzila, p-metoksibenzila, 9-fluorenilmetila, trimetilsilila, t-butildimetilsilila, i difenilmetila; i pri čemu postupak dodatno obuhvaća uklanjanje zaštite sa spoja formule 1 pri čemu je P1 karboksi zaštitna skupina.
28. Farmaceutski pripravak, naznačen time, da sadržava spoj u skladu s bilo kojim patentnim zahtjevom 1 do 26, i farmaceutski prihvatljivi nosač.
29. Farmaceutski pripravak u skladu s patentnim zahtjevom 28, naznačen time, da nadalje sadržava terapeutsko sredstvo odabrano od antagonista adenozinskih receptora, antagonista α-adrenergičkih receptora, antagonista β1-adrenergičkih receptora, agonista β2-adrenergičkih receptora, antagonista β-adrenergičkog receptora/ antagonista α1-receptora s dvostupanjskim djelovanjem, prekidači krajnjih proizvoda napredne glikacije, aldosteronski antagonisti, inhibitori aldosteronske sinteze, inhibitori aminopeptidaze N, androgeni, inhibitori enzima koji pretvara angiotenzin i inhibitori enzima / neprilizina koji pretvaraju angiotenzin dvostupanjskim djelovanjem, angiotenzin-konvertirajući enzim 2 aktivatori i stimulatori, vakcine angiotenzina-II, antikoagulansi, anti-dijabetička sredstva, antidiarrhealska sredstva, sredstva protiv glaukoma, anti-lipidna sredstva, antinociceptivna sredstva, anti-trombotska sredstva, AT1 receptor antagonisti i inhibitori antagonista / neprilizina AT1 receptora s dvostupanjskim djelovanjem i multifunkcionalni blokeri receptora angiotenzina, bradikinin antagonisti receptora, blokatori kalcijevih kanala, inhibitori kimaze, digoksin, diuretici, agonisti dopamina, inhibitori enzima koji pretvaraju endotelin, antagonisti receptora endotelina, inhibitori HMG-CoA reduktaze, estrogeni, agonisti receptora estrogena i / ili antagonisti, inhibitori ponovne pohrane monoamina, mišićni relaksanti, natriuretički peptidi i njihovi analozi, antagonisti receptora za uklanjanje natriuretskog peptida , inhibitori neprilizina, donore dušičnog oksida, nesteroidna protuupalna sredstva, antagonisti N-metil d-aspartat receptora, agonisti opioidnog receptora i inhibitori fosfodiesteraze, analozi prostaglandina, agonisti prostaglandinskih receptora, inhibitori renina, selektivni inhibitori ponovnog preuzimanja serotonina, blokator natrijevih kanala, topivi spojevi Gvanilat ciklaza stimulatori i aktivatori, triciklički antidepresivi, antagonisti receptora vazopresina, i njihove kombinacije.
30. Farmaceutski pripravak u skladu s patentnim zahtjevom 29, naznačen time, da je terapeutsko sredstvo antagonist AT1 receptora.
31. Spoj u skladu s bilo kojim patentnim zahtjevom 1 do 26, naznačen time, da se koristi za liječenje.
32. Spoj u skladu s patentnim zahtjevom 31, naznačen time, da se koristi za liječenje hipertenzije, zatajenja srca ili bubrežne bolesti.
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PT2964616T (pt) 2017-08-08
US20180194718A1 (en) 2018-07-12
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JP2016512195A (ja) 2016-04-25
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