ME02308B - Derivati benzilamina kao inhibitori kalikrein plazme - Google Patents

Derivati benzilamina kao inhibitori kalikrein plazme

Info

Publication number
ME02308B
ME02308B MEP-2016-6A MEP20166A ME02308B ME 02308 B ME02308 B ME 02308B ME P20166 A MEP20166 A ME P20166A ME 02308 B ME02308 B ME 02308B
Authority
ME
Montenegro
Prior art keywords
phenyl
aminomethyl
ethyl
benzylcarbamoyl
ethoxy
Prior art date
Application number
MEP-2016-6A
Other languages
English (en)
Inventor
David Michael Evans
Rebecca Louise Davie
David Philip Rooker
Hannah Joy Edwards
Original Assignee
Kalvista Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kalvista Pharmaceuticals Ltd filed Critical Kalvista Pharmaceuticals Ltd
Publication of ME02308B publication Critical patent/ME02308B/me

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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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 (15)

1. Jedinjenje formule I pri čemu:R1 je izabran kao H, alkil, -COalkil, -COaril, -COheteroaril, -CO2alkil, -(CH2)aOH, -(CH2)bCOOR10, -(CH2)cCONH2, -SO2alkil, -SO2aril, -SO2(CH2)hR13, -CO(CH2)iR14, -COcikloalkil, -COCH=CHR15, -CO(CH2)jNHCO(CH2)kR16 i -CONR17R18; R2 izabran je kao H i alkil;R3 je izabran kao H, alkil, -(CH2)daril, -(CH2)eheteroaril, -(CH2)fcikloalkil, -(CH2)gheterocikloalkil, -CH(cikloalkil)2, -CH(heterocikloalkil)2 i -(CH2)laril-O-(CH2)m-aril;R4 i R6 su nezavisno izabrani kao H i alkil;R5 je izabran kao H, alkil, alkoksi i OH;ili R4 i R5, zajedno sa atomom za koji su vezani mogu da se pridruže i formiraju 5- ili 6-očlanu azacikloalkil strukturu;R7 i R8 su nezavisno izabrani kao H, alkil, alkoksi, CN, halo and CF3;R9 je aril ili heteroaril;R10 je H ili alkil;a, b, c, d, e, f, g, h, i, j, l i m su nezavisno 1, 2 ili 3;k je 0, 1, 2 ili 3;*1 i *2 predstavljaju hiralne centre;alkil je linearni zasićen ugljovodonik koji ima do 10 ugljenikovih atoma (C1-C10) ili je razgranat zasićen ugljovodonik sa 3 do 10 ugljenikovih atoma (C3-C10); alkil može opciono da bude supstituisan sa 1 ili 2 supstituenata nezavisno izabranih kao (C3-C10)cikloalkil, (C1-C6)alkoksi, OH, CN, CF3, COOR11, fluoro i NR11R12;cikloalkil je mono- ili bi-ciklični zasićen ugljovodonik sa 3 do 10 ugljenikovih atoma;cikloalkil može opciono da bude vezan za aril grupu; ili je cikloalkil adamantil;heterocikloalkil je vezan za C-atom ili za N-atom sa 3 do 10 članova, zasićen, mono- ili biciklični prsten gde pomenuti prsten heterocikloalkila sadrži, gde je moguće, 1, 2 ili 3 heteroatoma nezavisno izabranih kao N, NR11 i O;alkoksi je linearan ugljovodonik vezan za O sa 1 do 6 ugljenikovih atoma (C1-C6) ili je razgranat ugljenikov atom sa 3 do 6 ugljenikovih atoma (C3-C6); alkoksi može opciono da bude supstituisan sa 1 ili 2 supstituenata nezavisno izabranih kao (C3-C10)cikloalkil, OH, CN, CF3, COOR11, fluoro i NR11R12;aril je fenil, bifenil ili naftil; aril može opciono da bude supstituisan sa do 5 supstituenata nezavisno izabranih kaoalkil, alkoksi, OH, halo, CN, COOR11, CF3 i NR11R12;heteroaril je 5, 6, 9 ili 10-očlani mono- ili bi-ciklični aromatični prsten, koji sadrži, gde je moguće, 1, 2 ili 3 članova prstena nezavisno izabranih kao N, NR11, S i O; heteroaril može opciono da bude supstituisan sa 1, 2 ili 3 supstituenata nezavisno izabranih kao alkil, alkoksi, OH, halo, CN, COOR11, CF3, NR11R12 i NHR19;R11 i R12 su nezavisno izabrani kao H i alkil;R13 je aril ili heteroaril;R14 je aril, heteroaril, cikloalkil ili heterocikloalkil;R15 je H, alkil, aril, heteroaril, cikloalkil ili heterocikloalkil;R16 je H, aril ili heteroaril;R17 je H, alkil, aril, heteroaril ili heterocikloalkil;R18 je -(CH2)mR21, gde je m 0, 1, 2 ili 3 i R21 je H, aril ili heteroaril;R19 -COalkil, -COaril ili -COheteroaril;i tautomeri, stereoizomeri (uključujući enantiomere, dijastereoizomere i racemske i neracemske smeše), farmaceutski prihvatljive soli i solvati, od njih.
2. Jedinjenje prema patentnom zahtevu 1, gde je R9 izabran od fenil i naftil, fenil može opciono da bude supstituisan sa do 3 supstituenata nezavisno izabranih od alkil, alkoksi, OH, halo, CN, COOR11, CF3 i NR11R12.
3. Jedinjenje ptema patentnom zahtevu 1 ili zahtevu 2, gde je R9 izabran od fenil, 1-naftalen, 2,4-dihlorofenil, 3,4-dihlorofenil, 3,4-difluorofenil, 4-hlorofenil, 4-trifluorometilfenil i 4-etoksifenil.
4. Jedinjenje prema bilo kom od patentnih zahteva od 1 do 3, gde je R1 izabran od H, - COaril, -COalkil, -CH2COOH, -SO2Ph i -SO2CH3.
5. Jedinjenje prema bilo kom od patentnih zahteva od 1 do 4, gde je R3 izabran od: i
6. Jedinjenje prema bilo kom od patentnih zahteva od 1 do 5, gde su R4 i R6 izabrani od H i CH3.
7. Jedinjenje prema bilo kom od patentnih zahteva od 1 do 6, gde je stereohemijska konfiguracija oko hiralnog centra *1 R.
8. Jedinjenje prema bilo kom od patentnih zahteva od 1 do 7, gde je stereohemijska konfiguracija oko hiralnog centra *2 S.
9. Jedinjenje prema bilo kom od patentnih zahteva od 1 do 8, gde je a 2 i b, c, d, e, f, g, h, j, I i m su 1.
10. Jedinjenje prema patentnom zahtevu 1, izabrano od: (S)-N-(4-aminometil-benzil)-2-[(R)-3-(4-etoksi-fenil)-2-propionilamino-propionilamino]-3-fenil-propionamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; {(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-cikloheksil-etilamino}-acetatna kiselina; (S)-N-(4-aminometil-3-fluoro-benzil)-2-[(R)-3-(4-etoksi-fenil)-2-propionilamino-propionilamino]-3-fenil- propionamid; (S)-N-(4-aminometil-2-hloro-benzil)-2-[(R)-3-(4-etoksi-fenil)-2-propionilamino-propionilamino]-3-fenil- propionamid; (S)-N-(4-aminometil-benzil)-3-(3,4-dihloro-fenil)-2-[(R)-3-(4-etoksi-fenil)-2-propionilamino-propionilamino]- propionamid; (S)-N-(4-aminometil-3-hloro-benzil)-2-[(R)-3-(4-etoksi-fenil)-2-propionilamino-propionilamino]-3-fenil- propionamid; (S)-N-(4-aminometil-benzil)-2-{[(R)-3-(4-etoksi-fenil)-2-propionilamino-propionil]-metil-amino}-3-fenil- propionamid; ({(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-cikloheksil-etil}-metil-amino)-acetatna kiselina; (S)-N-(4-aminometil-3-fluoro-benzil)-2-{[(R)-3-(4-etoksi-fenil)-2-propionilamino-propionil]-metil-amino}-3-fenil-propionamid; N-[(R)-1-{[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etil]-metil-karbamoil}-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-{[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etil]-metil-karbamoil}-2-(4-etoksi-fenil)-etil]-izobutiramid; Naftalen-1-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksifenil)-etil]-4-hloro-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-2,4-dihloro-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-3,4-difluoro-benzamid; (R)-2-amino-N-[(1S,2S)-1-(4-aminometil-benzilkarbamoil)-2-hidroksi-2-fenil-etil]-3-(4-etoksi-fenil)-propionamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-nikotinamid; (2S,3S)-N-(4-aminometil-benzil)-2-[(R)-3-(4-etoksi-fenil)-2-propionilamino-propionilamino]-3-hidroksi-3-fenil-propionamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-izonikotinamid; Tiofen-3-karboksilna kiselina-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)- 2-fenil-etilkarbamoil]-2-(4- etoksi-fenil)-etil]-amid; Tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4- etoksi-fenil)-etil]-amid; Cikloheksankarboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4- etoksi-fenil)-etil]-amid; Izoksazol-5-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4- etoksi-fenil)-etil]-amid; Piridin-2- karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2- fenil-etilkarbamoil]-2-(4- etoksi-fenil)-etil]-amid; Benzo[b]tiofen-2-karboksilna kiselina[(R)-1-[(S)-1-(4-ammometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; (R)-N-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etil]-2-(4-hloro-benzenesulfonilamino)-3-(4-etoksi-fenil)-propionamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-3-hloro-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-2-hloro-benzamid N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksifenil)-etil]-3-trifluorometil- benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-metil-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-3,4-dihloro-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-metoksi-benzamid; (S)-N-(4-aminometil-benzil)-2-[(R)-3-(4-etoksi-fenil)-2-(2-fenilacetilamino-acetilamino)-propionilamino]- 3-fenil-propionamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksifenil)-etil]-4-fluoro-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-6-metil-nikotinamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksifenil)-etil]-2-metil-nikotinamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksifenil)-etil]-2,6-dihloro-nikotinamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksifenil)-etil]-5,6-dihloro-nikotinamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-2,3,6-trifluoro-izonikotinamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksifenil)-etil]-3,3,3-trifluoro-propionamid; 2,4-dimetil-tiazol-5-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; 2-metil-tiazol-5-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; 3-hloro-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; 4-metil-tiazol-5-karboksilna kiselina[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; Furan-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4- etoksi-fenil)-etil]-amid; 3-metil-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-2-metoksi-izonikotinamid; 3-metil-1H-pirol-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; 3-amino-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-ammometil-benzilkarbamoil)-2-fenil-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-propoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-2-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(3,4-dihloro-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(4-hloro-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(4-fluoro-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(4-metoksi-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-4-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(3-fluoro-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-tiofen-2-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-tiofen-3-il-etilkarbamoil-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-tiazol-4-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-benzo[b]tiofen-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-3-fluoro-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-3-hloro-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; Piridin-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-tiofen-2-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-2-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-metoksi-benzamid; Piridin-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-3-hloro-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-metoksi-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(3,4-difluoro-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-izonikotinamid; Tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-2-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-hloro-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-2-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-metil-benzamid; Piridin-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(3,4-dihlorofenil)-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; (R)-N-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-2-il-etil]-3-(4-etoksi-fenil)-2-propionilaminopropionamid; N-[(R)-1-[(S)-1-(4-aminometil-3-fluoro-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-izonikotinamid; Piridin-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-3-fluoro-benzilkarbamoil)-2-fenil-etilkarbamoil)- 2-(4-etoksi-fenil)-etil]-amid; Tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(3,4-dihlorofenil)-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; (R)-N-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etil]-3-(4-etoksi-fenil)-2-propionilaminopropionamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(3,4-dihloro-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-izonikotinamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(3,4-dihloro-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-3,3,3-trifluoro-propionamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-hloro-benzamid; Izoksazol-5-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-metil-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(3,4-difluoro-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)- etil]-benzamid; 3-Hloro-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(1H-indol-3-il)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-benzo[b]tiofen-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-izonikotinamid; 3-Acetilamino-tiofen-2-karboksilna kiselina-[(R)-1-[(S)-1-(4-ammometil-benzilkarbamoil)-2-fenil-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(2-fluoro-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; 3-Metil-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-3-metil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; 3-amino-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-tiazol-4-il-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; 3-Hloro-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-tiazol-4-il-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-tiazol-4-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-metil-benzamid; 3-Metil-1H-pirol-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-benzo[b]tiofen-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; 3-amino-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-tiazol-4-il-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; 3-Acetilamino-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-benzo[b]tiofen- 3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-3-metil-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-2-metil-benzamid; 3,5-Dimetil-1H-pirol-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-3-metil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; 3-acetilamino-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-tiofen-3-il-etil karbamoil]-2-(4-etoksi-fenil)-etil]-amid; 3-amino-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-benzo[b]tiofen-3-il-etil karbamoil]-2-(4-etoksi-fenil)-etil]-amid; 3-acetilamino-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-benzo[b]tiofen- 3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; 3-hloro-tiofen-2-karboksilna kiselina [(R)-1-{[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etil]-metilkarbamoil}- 2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(1S,2R)-1-(4-aminometil-benzilkarbamoil)-2-hidroksi-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; 3-hloro-tiofen-2-karboksilna kiselina [(R)-1-[(1S,2R)-1-(4-aminometil-benzilkarbamoil)-2-hidroksi-2-fenil- etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; N-{(R,S)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-[4-(2,2,2-trifluoroetoksi)-fenil]-etil}-benzamid; i farmaceutski prihvatljive soli i solvati, od njih.
11. Jedinjenje prema patentnom zahtevu 1, izabrano od: N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksifenil)-etil]-benzamid; Naftalen-1-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksifenil)-etil]-4-hloro-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-2,4-dihloro-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-nikotinamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-3,4-difluoro-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2- (4-etoksi-fenil)-etil]-izonikotinamid; Tiofen-3-karboksilna kiselina-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)- 2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; Tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; Cikloheksankarboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; Izoksazol-5-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; Piridin-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2- fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; (R)-N-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etil]-2-(4-hlorobenzenesulfonilamino)-3-(4-etoksi-fenil)-propionamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-metil-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-3,4-dihloro-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksifenil)-etil]-3-hloro-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-metoksi-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-fluoro-benzamid; 3-metil-tiofen-2-karboksilna kiselina [(R)-]-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; 3-metil-1H-pirol-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; 3-amino-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-propoksifenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-2-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(3,4-dihloro-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(4-fluoro-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-tiofen-2-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-ammometil-benzilkarbamoil)-2-tiofen-3-il-etilkarbamoil-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-benzo[b]tiofen-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-3-fluoro-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-3-hloro-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; Piridin-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-tiofen-2-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-2-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-metoksi-benzamid; Piridin-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-3-hloro-benzilkarbamoil)-2-fenil-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-metoksi-benzamid; Tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-4-metil-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(3,4-difluoro-fenil)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; 3-hloro-tiofen-2-karboksilna kiselina [(R)-1-[(S)-11-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-amid; 3-Hloro-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-(1H-indol-3-il)-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-benzamid; N-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-benzo[b]tiofen-3-il-etilkarbamoil]-2-(4-etoksi-fenil)-etil]-izonikotinamid; 3-acetilamino-tiofen-2-karboksilna kiselina-[(R)-1-[(S)-1-(4-aminometil-benzilkarbamoil)-2-fenil-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; 3-metil-tiofen-2-karboksilna kiselina [(R)-1-[(S)-1(4-aminometil-benzilkarbamoil)-2-piridin-3-il-etilkarbamoil]- 2-(4-etoksi-fenil)-etil]-amid; i farmaceutski prihvatljive soli i njihovi solvati.
12. Farmaceutska kompozicija koja sadrži jedinjenje iz bilo kog od patentnih zahteva od 1 do 11 i farmaceutski prihvatljiv nosač, rastvarač ili ekscipijens.
13. Jedinjenje prema bilo kom od patentnih zahteva od 1 do 11 za upotrebu u medicini.
14. Jedinjenje prema bilo kojem od patentnih zahteva od 1 do 11 za upotrebu u metodi lečenja bolesti ili stanja koje implicira aktivnost kalikrein plazme, pri čemu bolest ili stanje kod koga je aktivnost kalikrein plazme implicirana jeste izabrano od gubitka vida, dijabetička retinopatije, dijabetički makularnog edema, naslednog angioedema, dijabetesa, pankreatitisa, cerebralnog krvarenja, nefropatijije, upalne bolesti bešike, artritisa, upale, septičkog šoka, hipotenzije, kancera, sondroma respiratornog poremećaja odraslih, diseminovana intravaskularna koagulacija, kardiopulmonarne bajpas operacije i postoperativnog krvarenja.
15. Jedinjenje za upotrebu prema patentnom zahtevu 14, gde bolesti ili stanja kod kojih implikacija kalikrein plazma aktivnosti jeste retinalna vaskularna permeabilnost povezana sa dijabetičkom retinopatijom i dijabetičkim makularnim edemom.
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