HRP20161177T1 - Modulator glukagonskog receptora - Google Patents

Modulator glukagonskog receptora Download PDF

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HRP20161177T1
HRP20161177T1 HRP20161177TT HRP20161177T HRP20161177T1 HR P20161177 T1 HRP20161177 T1 HR P20161177T1 HR P20161177T T HRP20161177T T HR P20161177TT HR P20161177 T HRP20161177 T HR P20161177T HR P20161177 T1 HRP20161177 T1 HR P20161177T1
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Croatia
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pharmaceutically acceptable
acceptable salt
compound according
substituted
independently
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HRP20161177TT
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Gary Erik Aspnes
Mary Theresa Didiuk
Kevin James Filipski
Angel Guzman-Perez
Esther Cheng Yin LEE
Jeffrey Allen Pfefferkorn
Benjamin Dawson STEVENS
Meihua Mike Tu
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Pfizer Inc.
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Publication of HRP20161177T1 publication Critical patent/HRP20161177T1/hr

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Claims (23)

1. Spoj Formule I [image] , ili njegova farmaceutski prihvatljiva sol, naznačen time što R1 je 5-eročlana heteroarilna skupina vezana bilo preko atoma ugljika ili dušika, te koja je izborno kondenzirana s (C4-C7)cikloalkilom, fenilom ili 6-eročlanim heteroarilom; gdje izborno kondenzirani 5-eročlani heteroaril može biti supstituiran s jednim do četiri supstituenta, od kojih se svakog neovisno bira između halogena, -S(O)2-(C1-C3)alkila, -S-(C1-C3)alkila, hidroksi, -C(O)NRaRb, (C3-C5)cikloalkila, cijano, fenila, koji može biti supstituiran s jednim do tri halogena, cijano, (C1-C3)alkila ili (C1-C3)alkoksi, 6-eročlanog heteroarila, koji može biti supstituiran s jednim do tri halogena, cijano, (C1-C3)alkila ili (C1-C3)alkoksi, (C1-C6)alkila, koji može biti supstituiran s jednim do tri fluora, ili (C1-C6)alkoksi, koji može biti supstituiran s jednim do tri fluora; svaki od Ra i Rb je neovisno H ili (C1-C3)alkil; R2 je H ili metil; R3 je tetrazolil, -CH2-tetrazolil, -(CH2)2SO3H ili -(CH2)2CO2H, -CH2CHFCO2H ili -CH2CHOHCO2H; svaki od A1, A2, A3 i A4 je neovisno CR4 ili N, uz uvjet da su najviše dva od A1, A2, A3 i A4 N; R4 je svaki put neovisno H, halogen, cijano, (C1-C3)alkil, koji može biti supstituiran s jednim do tri fluora, ili (C1-C3)alkoksi koji može biti supstituiran s jednim do tri fluora; L je -X-CH(R5)- ili -CH(R5)-X-; X je CH2, O ili NH; R5 je (C1-C6)alkil, koji može biti supstituiran s jednim do tri fluora, hidroksi ili metoksi; (C3-C7)cikloalkil, koji može biti supstituiran s jednim do dva (C1-C3)alkila, koji mogu biti supstituirani s jednim do tri fluora, te gdje se jedan do dva ugljika u (C3-C7)cikloalkilu može zamijeniti s NH, N(C1-C3)alkilom, O ili S; ili (C3-C7)cikloalkil-(C1-C6)alkil, gdje (C3-C7)cikloalkilna skupina u navedenom (C3-C7)cikloalkil-(C1-C6)alkilu može biti supstituirana s jednim do dva (C1-C3)alkila, koji mogu biti supstituirani s jednim do tri fluora; svaki od B1 B2, B3 i B4 je neovisno CR6 ili N, uz uvjet da su najviše dva od B1 B2, B3 i B4 N; i R6 je svaki put neovisno H, halogen, (C1-C3)alkil, koji može biti supstituiran s jednim do tri fluora, ili (C1-C3)alkoksi koji može biti supstituiran s jednim do tri fluora.
2. Spoj u skladu s patentnim zahtjevom 1, ili njegova farmaceutski prihvatljiva sol, naznačen time što je R1 5-eročlani heteroaril, vezan preko atoma dušika na ugljik između A1 i A4 u prstenu koji sadrži A1, A2, A3 i A4; R2 je vodik; i R3 je -(CH2)2CO2H.
3. Spoj u skladu s patentnim zahtjevom 1 ili 2, ili njegova farmaceutski prihvatljiva sol, naznačen time što je X O.
4. Spoj u skladu s patentnim zahtjevom 1 ili 2, ili njegova farmaceutski prihvatljiva sol, naznačen time što je X NH.
5. Spoj u skladu s patentnim zahtjevom 3 ili 4, ili njegova farmaceutski prihvatljiva sol, naznačen time što je L -X-CH(R5)-; svaki od A1, A2, A3 i A4 je neovisno CR4; ili A4 je N, a svaki od A1, A2 i A3 je CR4; ili svaki od A1 i A4 je N, a svaki od A2 i A3 je CR4; ili svaki od A2 i A4 je N, a svaki od A1 i A3 je CR4; R4 je svaki put neovisno H ili metil; svaki od B1 B2, B3 i B4 je CR6; ili B1 je N, a svaki od B2, B3 i B4 je CR6; ili B2 i B3 su svaki N, a svaki od B1 i B4 je CR6; ili svaki od B1 i B4 je N, a svaki od B2 i B3 je CR6; i R6 je svaki put H.
6. Spoj u skladu s patentnim zahtjevom 3, ili njegova farmaceutski prihvatljiva sol, naznačen time što je L -X-CH(R5)-; svaki od A1, A2, A3 i A4 je CR4; ili A4 je N, a svaki od A1, A2 i A3 je CR4; ili svaki od A1 i A4 je N, a svaki od A2 i A3 je CR4; ili svaki od A2 i A4 je N, a svaki od A1 i A3 je CR4; R4 je svaki put neovisno H ili metil; svaki od B1, B2, B3 i B4 je CR6; i R6 je svaki put neovisno H ili metil.
7. Spoj u skladu s patentnim zahtjevom 4, ili njegova farmaceutski prihvatljiva sol, naznačen time što je R2 vodik; R3 je -(CH2)2CO2H; L je -CH(R5)-X-; A4 je N, a svaki od A1, A2 i A3 je CR4; ili svaki od A1 i A4 je N, a svaki od A2 i A3 je CR4; ili svaki od A2 i A4 je N, a svaki od A1 i A3 je CR4; R4 je svaki put neovisno H ili metil; svaki od B1, B2, B3 i B4 je CR6; i R6 je svaki put neovisno H ili metil.
8. Spoj u skladu s patentnim zahtjevom 4, ili njegova farmaceutski prihvatljiva sol, naznačen time što je R2 vodik; R3 je -(CH2)2CO2H; L je -CH(R5)-X-; svaki od A1, A2, A3 i A4 je neovisno CR4; R4 je svaki put neovisno H ili metil; jedan od B1, B2, B3 i B4 je N, a svi ostali su CR6; i R6 je svaki put neovisno H ili metil.
9. Spoj u skladu s patentnim zahtjevima 5, 6, 7 ili 8, ili njegova farmaceutski prihvatljiva sol, naznačen time što je R5 etil, propil, izopropil, izobutil, neopentil, ciklopropil, ciklobutil, dimetilciklobutil, ciklopentil ili ciklopropilmetil.
10. Spoj u skladu s patentnim zahtjevom 9, ili njegova farmaceutski prihvatljiva sol, naznačen time što je R1 imidazolil, pirazolil, triazolil ili indazolil, koji može biti supstituiran s jednim do dva supstituenta, od kojih se svakog neovisno bira između metila, trifluormetila, etila, propila, izopropila, butila, t-butila, metoksi, etoksi, cijano, klora ili fluora.
11. Spoj u skladu s patentnim zahtjevom 1, ili njegova farmaceutski prihvatljiva sol, naznačen time što je R1 imidazolil, pirazolil, triazolil ili indazolil, koji može biti supstituiran s jednim do dva supstituenta, od kojih se svakog neovisno bira između metila, trifluormetila, etila, propila, izopropila, butila, t-butila, metoksi, etoksi, cijano, klora ili fluora; L je -X-CHR5-; X je O; a R5 je etil, propil, izopropil, izobutil, neopentil, ciklopropil, ciklobutil, dimetilciklobutil, ciklopentil ili ciklopropilmetil.
12. Spoj u skladu s patentnim zahtjevom 1, ili njegova farmaceutski prihvatljiva sol, naznačen time što je R1 imidazolil, pirazolil, triazolil ili indazolil, koji može biti supstituiran s jednim do dva supstituenta, od kojih se svakog neovisno bira između metila, trifluormetila, etila, propila, izopropila, butila, t-butila, metoksi, etoksi, cijano, klora ili fluora; L je -CHR5-X-; X je NH; a R5 je etil, propil, izopropil, izobutil, neopentil, ciklopropil, ciklobutil, dimetilciklobutil, ciklopentil ili ciklopropilmetil.
13. Spoj u skladu s patentnim zahtjevom 11 ili 12, ili njegova farmaceutski prihvatljiva sol, naznačen time što je R1 4-trifluormetilpirazol-1-il ili 4-trifluormetilimidazol-1-il.
14. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je (S)-3-(4-(1-(3,5-dimetil-4-(4-(trifluormetil)-1H-pirazol-1-il)fenoksi)butil)benzamido)propanska kiselina, ili njegova farmaceutski prihvatljiva sol.
15. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je (R)-3-(4-(ciklopentil(6-(4-(trifluormetil)-1H-pirazol-1-il)piridin-3-ilamino)metil)benzamido)propanska kiselina, ili njezina farmaceutski prihvatljiva sol.
16. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je (R)-3-(4-(1-(6-(4-terc-butil-1H-pirazol-1-il)piridin-3-ilamino)butil)benzamido)propanska kiselina, ili njezina farmaceutski prihvatljiva sol.
17. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je (R)-3-(4-((3,3-dimetilciklobutil)(2-(4-(trifluormetil)-1H-pirazol-1-il)pirimidin-5-iloksi)metil)benzamido)propanska kiselina, ili njezina farmaceutski prihvatljiva sol.
18. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je (S)-3-(4-(ciklopentil(6-(4-(trifluormetil)-1H-pirazol-1-il)piridin-3-ilamino)metil)benzamido)propanska kiselina, ili njezina farmaceutski prihvatljiva sol.
19. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je (S)-3-(4-(1-(6-(4-terc-butil-1H-pirazol-1-il)piridin-3-ilamino)butil)benzamido)propanska kiselina, ili njezina farmaceutski prihvatljiva sol.
20. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je (S)-3-(4-((3,3-dimetilciklobutil)(2-(4-(trifluormetil)-1H-pirazol-1-il)pirimidin-5-iloksi)metil)benzamido)propanska kiselina, ili njezina farmaceutski prihvatljiva sol.
21. Farmaceutski pripravak, naznačen time što sadrži (i) terapijski djelotvornu količinu spoja u skladu s bilo kojim od patentnih zahtjeva 1 do 20; ili njegovu farmaceutski prihvatljivu sol i (ii) farmaceutski prihvatljivu pomoćnu tvar, razrjeđivač ili podlogu.
22. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 20 ili farmaceutski pripravak u skladu s patentnim zahtjevom 21, naznačeni time što su namijenjeni upotrebi kao medikament.
23. Spoj, ili njegova farmaceutski prihvatljiva sol, u skladu s bilo kojim od patentnih zahtjeva 1 do 21, ili farmaceutski pripravak u skladu s patentnim zahtjevom 21, naznačeni time što su namijenjeni upotrebi u postupku liječenja ili odgađanja napredovanja ili početka dijabetesa tip 2 i poremećaja povezanih s dijabetesom kod životinja.
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