HRP20140714T1 - Alkilamin-supstituirani dicijanopiridin i njegovi esterski amino kiselinski predlijekovi - Google Patents

Alkilamin-supstituirani dicijanopiridin i njegovi esterski amino kiselinski predlijekovi Download PDF

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HRP20140714T1
HRP20140714T1 HRP20140714AT HRP20140714T HRP20140714T1 HR P20140714 T1 HRP20140714 T1 HR P20140714T1 HR P20140714A T HRP20140714A T HR P20140714AT HR P20140714 T HRP20140714 T HR P20140714T HR P20140714 T1 HRP20140714 T1 HR P20140714T1
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represents hydrogen
image
formula
methyl
solvates
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Alexandros Vakalopoulos
Daniel Meibom
Barbara ALBRECHT-KÜPPER
Katja Zimmermann
Joerg Keldenich
Hans-Georg Lerchen
Peter Nell
Frank SÜSSMEIER
Ursula Krenz
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Bayer Intellectual Property Gmbh
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Claims (36)

1. Spojevi sa formulom (I) [image] naznačeni time da R1 predstavlja (C1-C4)-alkil, R2 predstavlja (C1-C6)-alkil, (C2-C4)-alkenil, (C2-C4)-alkinil ili (C3-C7)-cikloalkil, gdje (C1-C6)-alkil može biti supstituiran sa 1 do 3 supstituenta međusobno neovisno odabrana iz skupine koja sadrži fluor, klor, trifluorometil, trifluorometoksi, (C1-C4)-alkoksi, (C3-C7)-cikloalkil, (C3-C7)-cikloalkoksi, (C1-C4)-alkilsulfanil i (C1-C4)-alkilsulfonil, i gdje (C2-C4)-alkenil i (C2-C4)-alkinil mogu biti supstituirani sa 1 ili 2 supstituenta međusobno neovisno odabrana iz skupine koja sadrži fluor, trifluorometil, (C1-C4)-alkil, trifluorometoksi i (C1-C4)-alkoksi, i gdje (C3-C7)-cikloalkil može biti supstituiran sa 1 ili 2 supstituenta međusobno neovisno odabrana iz skupine koja sadrži fluor, klor, trifluorometil, (C1-C4)-alkil, trifluorometoksi i (C1-C4)-alkoksi, ili R1 i R2 zajedno s atomom dušika na koji su vezani tvore 4- do 7-člani heterocikal koji može sadržavati dodatni heteroatom iz skupine koja sadrži N, O i S, gdje 4- do 7-člani heterocikal može biti supstituiran sa 1 ili 2 supstituenta međusobno neovisno odabrana iz skupine koja sadrži fluor, klor, okso, trifluorometil, (C1-C4)-alkil, trifluorometoksi i (C1-C4)-alkoksi, R3 predstavlja vodik ili skupinu sa formulom [image] gdje # predstavlja točku vezanja na atom kisika, L1 predstavlja (C2-C6)-alkandiil, L2 predstavlja (C2-C6)-alkandiil, R4 predstavlja vodik ili bočnu skupinu prirodne α-amino kiseline ili njezine homologe ili izomere, R5 predstavlja vodik ili metil, R6 predstavlja vodik ili (C1-C4)-alkil, R7 predstavlja vodik ili (C1-C4)-alkil, ili R6 i R7 zajedno s atomom dušika na koji su vezani tvore 5- ili 6-člani heterocikal, gdje 5- ili 6-člani heterocikal može biti supstituiran sa 1 ili 2 supstituenta neovisno odabrana iz skupine koju čine (C1-C4)-alkil, amino, hidroksil i (C1-C4)-alkoksi, ili R7 zajedno s R4 i atomi, na koje su oni vezani, tvore pirolidinski ili piperidinski prsten, R8 predstavlja vodik ili bočnu skupinu prirodne α-amino kiseline ili njezine homologe ili izomere, R9 predstavlja vodik ili metil, R10 predstavlja vodik ili metil, R11 predstavlja vodik ili bočnu skupinu prirodne α-amino kiseline ili njezine homologe ili izomere, R12 predstavlja vodik ili metil, R13 predstavlja vodik ili (C1-C4)-alkil, R14 predstavlja vodik ili (C1-C4)-alkil, ili R13 i R14 zajedno s atomom dušika na koji su vezani tvore 5- ili 6-člani heterocikal, gdje 5- ili 6-člani heterocikal može biti supstituiran sa 1 ili 2 supstituenta neovisno odabrana iz skupine koju čine (C1-C4)-alkil, amino, hidroksil i (C1-C4)-alkoksi, ili R14 zajedno s R11 i atomi, na koje su oni vezani, tvore pirolidinski ili piperidinski prsten, R15 predstavlja vodik ili (C1-C4)-alkil, R16 predstavlja vodik ili (C1-C4)-alkil, ili R15 i R16 zajedno s atomom dušika na koji su vezani tvore 5- ili 6-člani heterocikal, gdje 5- ili 6-člani heterocikal može biti supstituiran sa 1 ili 2 supstituenta neovisno odabrana iz skupine koju čine (C1-C4)-alkil, amino, hidroksil i (C1-C4)-alkoksi, R17 predstavlja vodik ili (C1-C4)-alkil, R18 predstavlja vodik ili (C1-C4)-alkil, ili R17 i R18 zajedno s atomom dušika na koji su vezani tvore 5- ili 6-člani heterocikal, gdje 5- ili 6-člani heterocikal može biti supstituiran sa 1 ili 2 supstituenta neovisno odabrana iz skupine koju čine (C1-C4)-alkil, amino, hidroksil i (C1-C4)-alkoksi, R19 predstavlja vodik ili metil, kao i njihove soli i solvati.
2. Spojevi sa formulom (I) prema zahtjevu 1 naznačeni time da R1 predstavlja metil ili etil, R2 predstavlja (C1-C3)-alkil, ciklopropil ili ciklobutil, gdje (C1-C3)-alkil može biti supstituiran sa 1 ili 2 supstituenta međusobno neovisno odabrana iz skupine koju čine fluor, klor, trifluorometil, metoksi, etoksi, ciklopropil i ciklobutil, ili R1 i R2 zajedno s atomom dušika na koji su vezani tvore 4- do 6-člani heterocikal koji može sadržavati dodatni heteroatom iz skupine koja sadrži N, O i S, gdje 4- do 6-člani heterocikal može biti supstituiran sa 1 ili 2 supstituenta međusobno neovisno odabrana iz skupine koja sadrži fluor, trifluorometil, metil, etil, metoksi i etoksi, R3 predstavlja vodik ili skupinu sa formulom [image] gdje # predstavlja točku vezanja na atom kisika, L1 predstavlja etan-1,2-diil, L2 predstavlja etan-1,2-diil, R4 predstavlja metil ili 3-aminopropan-1-il, R5 predstavlja vodik, R6 predstavlja vodik, R7 predstavlja vodik, R8 predstavlja metil ili 2-metilpropan-1-il, R9 predstavlja vodik, R10 predstavlja vodik, R11 predstavlja metil, 1-metilpropan-1-il, imidazol-4-ilmetil, 4-aminobutan-1-il, 3-amino-propan-1-il, 2-aminoetil, aminometil ili 3-gvanidinopropan-1-il, R12 predstavlja vodik, R13 predstavlja vodik, R14 predstavlja vodik, ili R14 zajedno s R11 i atomi, na koje su oni vezani, tvore pirolidinski prsten, R15 predstavlja vodik, R16 predstavlja vodik, R17 predstavlja vodik, R18 predstavlja vodik, R19 predstavlja vodik, kao i njihove soli, solvati i solvati njihovih soli.
3. Spojevi sa formulom (I) prema zahtjevu 1 ili 2 naznačeni time da R1 predstavlja metil ili etil, R2 predstavlja metil, etil ili n-propil, gdje metil, etil i n-propil može biti supstituiran sa 1 ili 2 supstituenta međusobno neovisno odabrana iz skupine koja sadrži fluor, trifluorometil i metoksi, ili R1 i R2 zajedno s atomom dušika na koji su vezani tvore azetidinil, pirolidinil ili piperidinil prsten, gdje azetidinil i piperidinil prsten može biti supstituiran sa metoksi supstituentom, R3 predstavlja vodik, kao i njihove soli, solvati i solvati njihovih soli.
4. Spojevi sa formulom (I) prema zahtjevu 1 ili 2 naznačeni time da R1 i R2 zajedno s atomom dušika na koji su vezani tvore azetidinil, pirolidinil ili piperidinil prsten, gdje azetidinil i piperidinil prsten može biti supstituiran sa metoksi supstituentom, R3 predstavlja skupinu sa formulom [image] gdje # predstavlja točku vezanja na atom kisika, L1 predstavlja etan-1,2-diil, R8 predstavlja metil ili izobutil, R9 predstavlja vodik, R10 predstavlja vodik, R11 predstavlja vodik, metil, 1-metilpropan-1-il, 4-aminobutan-1-il ili 3-gvanidinopropan-1-il, R12 predstavlja vodik, R13 predstavlja vodik, R14 predstavlja vodik, ili R14 zajedno s R11 i atomi, na koje su oni vezani, tvore pirolidinski prsten, R15 predstavlja vodik, R16 predstavlja vodik, kao i njihove soli, solvati i solvati njihovih soli.
5. Spojevi sa formulom (I) prema zahtjevu 1 naznačeni time da R1 i R2 zajedno s atomom dušika na koji su vezani tvore pirolidinilni prsten, R3 predstavlja skupinu sa formulom [image] gdje # predstavlja točku vezanja na atom kisika, L1 predstavlja etan-1,2-diil, R8 predstavlja metil ili izobutil, R9 predstavlja vodik, R10 predstavlja vodik, R11 predstavlja vodik, metil, 1-metilpropan-1-il, 4-aminobutan-1-il ili 3-gvanidinopropan-1-il, R12 predstavlja vodik, R13 predstavlja vodik, R14 predstavlja vodik, ili R14 zajedno s R11 i atomi, na koje su oni vezani, tvore pirolidinski prsten, R15 predstavlja vodik, R16 predstavlja vodik, kao i njihove soli, solvati i solvati njihovih soli.
6. Spojevi sa formulom (I) prema zahtjevu 1 naznačeni time da R1 i R2 zajedno s atomom dušika na koji su vezani tvore azetidinil, pirolidinil ili piperidinil prsten, kao i njihove soli, solvati i solvati njihovih soli.
7. Spojevi sa formulom (I) prema zahtjevu 1 naznačeni time da R1 i R2 zajedno s atomom dušika na koji su vezani tvore pirolidinilni prsten, R3 predstavlja skupinu sa formulom [image] gdje # predstavlja točku vezanja na atom kisika, R8 predstavlja metil, R9 predstavlja vodik, R10 predstavlja vodik, R11 predstavlja metil ili 1-metilpropan-1-il, R12 predstavlja vodik, R13 predstavlja vodik, R14 predstavlja vodik, kao i njihove soli, solvati i solvati njihovih soli.
8. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-(azetidin-1-il)-6-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-4-[4-(2-hidroksietoksi)fenil]piridin-3,5-dikarbonitril kao i njegove soli i/ili solvati.
9. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-((3-metoksi)-azetidin-1-il)-6-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-4-[4-(2-hidroksietoksi)fenil]piridin-3,5-dikarbonitril kao i njegove soli i/ili solvati.
10. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-6-(4,4-difluoropiperidin-1-il)-4-[4-(2-hidroksietoksi)fenil]piridin-3,5-dikarbonitril kao i njegove soli i/ili solvati.
11. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-4-[4-(2-hidroksi-etoksi)fenil]-6-(piridin-1-il)piridin-3,5-dikarbonitril kao i njegove soli i/ili solvati.
12. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-4-[4-(2-hidroksi-etoksi)fenil]-6-(pirolidin-1-il)piridin-3,5-dikarbonitril kao i njegove soli i/ili solvati.
13. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-{4-[2-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-3,5-dicijano-6-(pirolidin-1-il)piridin-4-il]fenoksi}etil L-alaninat trifluoroacetat kao i njegovi solvati.
14. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-{4-[2-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-3,5-dicijano-6-(pirolidin-1-il)piridin-4-il]fenoksi}etil L-alanil L-alaninat hidroklorid kao i njegovi solvati.
15. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-{4-[2-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-3,5-dicijano-6-(pirolidin-1-il)piridin-4-il]fenoksi}etil L-izoleucil L-alaninat hidroklorid kao i njegovi solvati.
16. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-6-(dietilamino)-4-[4-(2-hidroksietoksi)fenil]piridin-3,5-dikarbonitril kao i njegove soli i/ili solvati.
17. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-{4-[2-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-3,5-dicijano-6-(pirolidin-1-il)piridin-4-il]fenoksi}etil L-lizil-beta-alaninat dihidroklorid kao i njegove soli i/ili solvati.
18. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-{4-[2-(azetidin-1-il)-6-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-3,5-dicijanopiridin-4-il]fenoksi}etil L-lizil-1-alaninat bis(trifluoroacetat) kao i njegovi solvati.
19. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-{4-[2-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-3,5-dicijano-6-(pirolidin-1-il)piridin-4-il]fenoksi}etil glicil-1-leucinat hidroklorid kao i njegovi solvati.
20. Spoj prema zahtjevu 1, naznačen time da spoj ima dolje navedenu strukturu [image] 2-({[2-(4-klorofenil)-1,3-tiazol-4-il]metil}sulfanil)-4-[4-(2-hidroksi-etoksi)fenil]-6-[(2-metoksietil)(metil)amino]piridin-3,5-dikarbonitril kao i njegove soli i/ili solvati.
21. Postupak za pripravu spojeva sa formulom (I) kako je definirano u bilo kojem zahtjevu od 1 do 3 gdje R3 predstavlja vodik, naznačen time da se spoj sa formulom (II) [image] početno pretvara sa bakrovim(II) kloridom i izoamil nitritom u prikladnom otapalu u spoj sa formulom (III) [image] i ovo tada, u inertnom otapalu, ako je prikladno u prisutnosti pogodne baze, reagira sa spojem sa formulom (IV) [image] u kojem R1 i R2 svaki imaju značenja navedena u bilo kojem od patentnih zahtjeva 1 do 3, da se dobije spoj sa formulom (I-A) [image] u kojem R1 i R2 svaki imaju značenja navedena u bilo kojem od patentnih zahtjeva 1 do 3, zatim se bilo koje prisutne zaštitne skupine odstranjuju i dobiveni spojevi sa formulom (I), ako je prikladno, pretvaraju se sa odgovarajućim (i) otapalima i/ili (ii) bazama ili kiselinama u njihove solvate, soli i/ili solvate soli.
22. Postupak za pripravu spojeva sa formulom (I) kako je definirano u bilo kojem zahtjevu 1, 2, 4, 5, 6 i 7 gdje R3 predstavlja skupinu sa formulom [image] gdje L1, L2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 i R19 svaki imaju značenja navedena u bilo kojem od patentnih zahtjeva 1, 2, 4, 5, 6 i 7, naznačen time da [A] spoj sa formulom (I-A) [image] u kojem R1 i R2 svaki imaju značenja navedena u bilo kojem od patentnih zahtjeva 1, 2, 4, 5, 6 i 7, se početno spaja u inertnom otapalu u prisutnosti sredstva za kondenzaciju sa karboksilnom kiselinom sa formulom (V) ili (VI) [image] gdje L2, R4 i R5 svaki imaju značenja navedena u bilo kojem od patentnih zahtjeva 1, 2, 4, 5, 6 i 7 i R6A, R7A, R17A i R18A svaki imaju odgovarajuća značenja navedena za R6, R7, R17 i R18, ili predstavljaju amino zaštitnu skupinu, kao što je, na primjer, tert-butoksikarbonil, da se dobije spoj sa formulom (VII) ili (VIII) [image] ili [image] gdje L2, R1, R2, R4, R5, R6A, R7A, R17A i R18A svaki imaju gore navedena značenja, i zatim se bilo koje prisutne zaštitne skupine odstranjuju da se dobije spoj sa formulom (I-B) ili (I-C) [image] ili [image] gdje L2, R1, R2, R4, R5, R6, R7, R17 i R18 svaki imaju značenja navedena u bilo kojem od patentnih zahtjeva 1, 2, 4, 5, 6 i 7, ili [B] spoj sa formulom (I-A) se početno spaja u inertnom otapalu u prisutnosti sredstva za kondenzaciju sa karboksilnom kiselinom sa formulom (IX), (X), (XI) ili (XII) [image] [image] gdje L1, L2, R8, R9, R10, R11, R12 i R19 svaki imaju značenja navedena u bilo kojem od patentnih zahtjeva 1, 2, 4, 5, 6 i 7 i R13A, R14A, R15A i R16A svaki imaju odgovarajuća značenja navedena za R13, R14, R15 i R16, ili predstavljaju amino zaštitnu skupinu, kao što je, na primjer, tert-butoksikarbonil, da se dobiju spojevi sa formulom (XIII), (XIV), (XV) ili (XVI) [image] [image] [image] ili [image] gdje L1, L2, R1, R2, R8, R9, R10, R11, R12, R13A, R14A, R15A, R16A i R19 svaki imaju gore navedena značenja, te se zatim bilo koje prisutne zaštitne skupine odstranjuju da se dobije spoj sa formulom (I-D), (I-E), (I-F) ili (I-G) [image] [image] [image] ili [image] u kojem L1, L2 R1, R2, R8, R9, R10, R11, R12, R13, R14, R15, R16 i R19 svaki imaju značenja navedena u bilo kojem od patentnih zahtjeva 1, 2, 4, 5, 6 i 7, ili [C] amino zaštitna skupina se uklanja iz spoja sa formulom (VII-1) ili (VIII-1) [image] ili [image] gdje L2, R1, R2, R4, R5, R7 i R17 svaki imaju značenja navedena u bilo kojem od patentnih zahtjeva 1, 2, 4, 5, 6 i 7, i R6A i R18A predstavljaju amino zaštitnu skupinu, na primjer tert-butoksikarbonil, standardnim postupcima da se dobije spoj sa formulom (I-B-1) ili (I-C-1) [image] ili [image] gdje L2, R1, R2, R4, R5, R7 i R17 svaki imaju značenja navedena u bilo kojem od patentnih zahtjeva 1, 2, 4, 5, 6 i 7, i oni se početno spajaju u inertnom otapalu u prisutnosti sredstva za kondenzaciju sa karboksilnom kiselinom sa formulom (XVII) ili (XVIII) [image] gdje L1, R11 i R12 svaki imaju značenja navedena u bilo kojem od patentnih zahtjeva 1, 2, 4, 5, 6 i 7 i R13A, R14A, R15A i R16A svaki imaju odgovarajuća značenja navedena za R13, R14, R15 i R16, ili predstavljaju amino zaštitnu skupinu, kao što je, na primjer, tert-butoksikarbonil, da se dobiju spojevi sa formulom (XIII), (XIV), (XV) ili (XVI), te se zatim bilo koje prisutne zaštitne skupine ponovno odstranjuju kako bi se dobili odgovarajući spojevi (I-D), (I-E), (I-F) ili (I-G), a dobiveni se spojevi sa formulom (I-B), (I-C), (I-D), (I-E), (I-F) i (I-G), ako je prikladno, pretvaraju s odgovarajućim (i) otapalima i/ili (ii) bazama ili kiselinama u njihove solvate, soli i/ili solvate soli.
23. Agonisti adenozin A1 receptora sa formulom (I) kako je definirano u bilo kojem zahtjevu 1 do 20 naznačeni time da su za uporabu za liječenje i/ili sprječavanje bolesti.
24. Agonisti adenozin A1 receptora sa formulom (I) kako je definirano u bilo kojem zahtjevu 1 do 20 naznačeni time da su za uporabu u postupku liječenja i/ili sprječavanja koronarne bolesti srca, akutnog koronarnog sindroma, angine pektoris, zatajenja srca, infarkta miokarda i fibrilacije atrija.
25. Agonisti adenozin A1 receptora sa formulom (I) kako je definirano u bilo kojem zahtjevu 1 do 20 naznačeni time da su za uporabu u postupku liječenja i/ili sprječavanja dijabetesa, metaboličkog sindroma i dislipidemija.
26. Agonisti adenozin A1 receptora sa formulom (I) prema zahtjevu 1 naznačeni time da su za uporabu u postupku liječenja i/ili sprječavanja bolesti bubrega.
27. Uporaba agonista adenozin A1 receptora sa formulom (I) kako je definirano u bilo kojem zahtjevu 1 do 20 naznačena time da je za pripravu medikamenta za liječenje i/ili sprječavanje koronarne bolesti srca, akutnog koronarnog sindroma, angine pektoris, zatajenja srca, infarkta miokarda i fibrilacije atrija.
28. Uporaba agonista adenozin A1 receptora sa formulom (I) kako je definirano u bilo kojem zahtjevu 1 do 20 naznačena time da je za pripravu medikamenta za liječenje i/ili sprječavanje akutnog i kroničnog zatajenja srca, dekompenzacijskog zatajenja srca, zatajenja desne strane srca, zatajenja lijeve strane srca, globalnog zatajenja, ishemijske kardiomiopatije, dilatacijske kardiomiopatije, prirođenih srčanih grešaka, grešaka srčanih zalistaka, zatajenje srca povezanog sa greškama srčanih zalistaka, mitralne stenoze, mitralne insuficijencije, stenoze aorte, insuficijencije aorte, trikuspidne stenoze, trikuspidne insuficijencije, pulmonalne stenoze, insuficijencije plućnih zalistaka, kombiniranog oštećenja srčanih zalistaka, upale miokarda (miokarditisa), kroničnog miokarditisa, akutnog miokarditisa, virusnog miokarditisa, dijabetičkog zatajenja srca, alkoholne kardiomiopatije, poremećaja kardijalne pohrane, te dijastoličkog i sistoličkog zatajenja srca, te akutnih faza pogoršanja zatajenja srca.
29. Uporaba agonista adenozin A1 receptora sa formulom (I) kako je definirano u zahtjevu 1 naznačena time da je za pripravu medikamenta za liječenje i/ili sprječavanje bolesti bubrega.
30. Uporaba agonista adenozin A1 receptora sa formulom (I) kako je definirano u bilo kojem zahtjevu 1 do 20 naznačena time da je za pripravu medikamenta za liječenje i/ili sprječavanje dijabetesa, metaboličkog sindroma i dislipidemija.
31. Medikament, naznačen time da sadrži agonist adenozin A1 receptora sa formulom (I) kako je definirano u bilo kojem zahtjevu 1 do 20 u kombinaciji sa inertnom netoksičnom farmaceutski prikladnom pomoćnom tvari.
32. Medikament, naznačen time da sadrži agonist adenozin A1 receptora sa formulom (I) kako je definirano u bilo kojem zahtjevu 1 do 20 naznačen time da je u kombinaciji sa jednim ili više dodatnih aktivnih sastojaka odabranih iz skupine koja se sastoji od aktivnih sastojaka za izmjenu metabolizma lipida, antidijabetika, antihipertenzijskih lijekova i antitrombotskih lijekova.
33. Medikament prema zahtjevu 31 ili 32 naznačen time da je za uporabu za liječenje i/ili sprječavanje koronarne bolesti srca, akutnog koronarnog sindroma, angine pektoris, zatajenja srca, infarkta miokarda i fibrilacije atrija.
34. Medikament prema zahtjevu 31 ili 32 naznačen time da je za uporabu za liječenje i/ili sprječavanje akutnog i kroničnog zatajenja srca, dekompenzacijskog zatajenja srca, zatajenja desne strane srca, zatajenja lijeve strane srca, globalnog zatajenja, ishemijske kardiomiopatije, dilatacijske kardiomiopatije, prirođenih srčanih grešaka, grešaka srčanih zalistaka, zatajenje srca povezanog sa greškama srčanih zalistaka, mitralne stenoze, mitralne insuficijencije, stenoze aorte, insuficijencije aorte, trikuspidne stenoze, trikuspidne insuficijencije, pulmonalne stenoze, insuficijencije plućnih zalistaka, kombiniranog oštećenja srčanih zalistaka, upale miokarda (miokarditisa), kroničnog miokarditisa, akutnog miokarditisa, virusnog miokarditisa, dijabetičkog zatajenja srca, alkoholne kardiomiopatije, poremećaja kardijalne pohrane, te dijastoličkog i sistoličkog zatajenja srca, te akutnih faza pogoršanja zatajenja srca.
35. Medikament prema zahtjevu 31 ili 32 naznačen time da je za uporabu za liječenje i/ili sprječavanje dijabetesa, metaboličkog sindroma i dislipidemija.
36. Medikament prema zahtjevu 31 ili 32 naznačen time da je za uporabu za liječenje i/ili sprječavanje bolesti bubrega.
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