SI3140296T1 - Pirolidin gpr40 modulatorji za zdravljenje bolezni kot je sladkorna bolezen - Google Patents
Pirolidin gpr40 modulatorji za zdravljenje bolezni kot je sladkorna bolezen Download PDFInfo
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Claims (15)
- PIROLIDIN GPR40 MODULATORJI ZA ZDRAVLJENJE BOLEZNI KOT JE SLADKORNA BOLEZEN PATENTNI ZAHTEVKI1. Spojina s formulo (I):ali njena stereoizomera, tavtomera, farmacevtsko sprejemljiva sol, polimorf ali solvat, kjer: X je neodvisno izbran izmed:, O, S, NH, N(Ci-4 alkila), CH2, CH2CH2, CH(Ci-4 alkila), OCH2, CH2O OCH2CH2, in CH2CH2O obroč A je neodvisnoobroč B je neodvisno 4- do 7- členski nasičen heterocikel, ki vsebuje atome ogljika, atom dušika, prikazan v obroču B, in 0-1 dodaten heteroatom, izbran izmed N, O in S; in obroč B je substituiran z 0-4 R2; R1 je neodvisnofenil, benzil, naftil ali 5- do 10-členski heteroaril, ki vsebujejo atome ogljika, in 1-4 heteroatome, izbrane izmed N, NR11, O in S; pri čemer so omenjeni fenil, benzil, naftil in heteroaril vsakokrat substituirani z 0-3 R6; R2 je v vsakem primeru neodvisno izbran izmed: = O, OH, halogena, C1-6 alkila, substituiranega z 0-1 R12, C1-6 alkoksija substituiranega z 0-1 R12, Ci-4 haloalkila, substituiranega z 0-1 R12, C1-4 haloalkoksija, substituiranega z 0-1 R12, - (CH2) m- C3-6 karbocikla, substituiranega z 0-1 R12, in - (CH2)m- (5- do 10-členski heteroaril, ki vsebuje ogljikove atome in 1- 4 heteroatome, izbrane izmed N, NR11, O in S); kjer je omenjeni heteroaril substituiran z 0-1 R12; kadar sta dve skupini R2 vezani na dva različna ogljikova atoma, se lahko združita, da tvorita 1- do 3-členski ogljikov atomski most nad obročem B; kadar sta dve skupini R2 vezani na isti ogljik, lahko skupaj z ogljikovim atomom, na katerega sta vezana, tvorita 3- do 6-členski ogljikov atom, ki vsebuje spiro obroč; R3 je neodvisno izbran izmed: C1-6 alkila substituiranega z R10, C2-6 alkenila substituiranega z R10, C2-6 alkinila substituiranega z R10 C1-4 haloalkila substituiranega z R10, -0(CH2)i-20(CH2)i-4R10, OR9, SR9, C(0)OR9, CO2R9, S(0)R9, SO2R9, in CONHR9; R4 in R4a sta neodvisno izbrana izmed: H, halogena, C1-6 alkila, C1-6 alkoksija, in -(CH2)m-C3-6 karbocikla; R5 je v vsakem primeru, neodvisno izbran izmed: halogena, C1-6 alkila, C1-6 alkoksija, C1-6 haloalkila, in C1-6 haloalkoksija; R6, je v vsakem primeru, neodvisno izbran izmed: halogena, OH, C1-4 alkiltia, CN, S02(Ci-2 alkila), N(Ci-4alkila)2, C1-4 haloalkila, C1-4 haloalkoksija, C1-8 alkila substituiranega z 0-1 R7, C1-6 alkoksija substituiranega z 0-1 R7, -(0)n-(CH2)m-(C3-io karbocikel, substituiran z 0- 2 R7), in -(CH2)m-(5- do 10-členski heteroaril ki vsebuje atome ogljika in 1- 4 heteroatome izbrane izmed N, NR11, O, in S); kjer je omenjeni heteroaril substituiran z 0-2 R7; R7, je v vsakem primeru neodvisno izbran izmed: halogena, OH, C1-4 alkila, C2-4 alkenila, C1-4 alkoksija, C-m alkiltia, C1-4 haloalkila, Cm haloalkoksija, SCF3, CN, NO2, NH2, NH(Cm alkila), N(Cm alkila)2, S02(Ci-2 alkila), in fenila; R8 je neodvisno izbran izmed: H in Cm alkila; R9, je v vsakem primeru neodvisno izbran izmed: C1-6 alkila substituiranega z R10, in Cm haloalkila substituiranega z R10; R10, je v vsakem primeru neodvisno izbran izmed: CN, Cm alkoksija, Cm haloalkoksija, C02(Cm alkila), S02(Cm alkila), in tetrazolila; R11, je v vsakem primeru neodvisno izbran izmed: H, Cm alkila in benzila R12, je v vsakem primeru neodvisno izbran izmed: OH, halogena, CN, Cm alkila, Cm alkoksija, Cm haloalkila, Cm haloalkoksija, C02(Cm alkila), in tetrazolila; m, je v vsakem primeru neodvisno 0, 1, ali 2; in n, je v vsakem primeru neodvisno 0 ali 1.
- 2. Spojina po zahtevku 1, kjer je R4 vodik in R8 je vodik, nadalje označena s formulo (II):ali njena stereoizomera, tavtomera, farmacevtsko sprejemljiva sol, polimorf ali solvat, kjer:: Xje neodvisno izbran izmed: O, N(CH3), CH2, CH2O in CH2CH2O; obroč A je neodvisnoobroč B je neodvisno 4- do 7-členski nasičeni heterocikel, ki vsebuje atome ogljika in dušikov atom prikazan v obroču B; in obroč B je substituiran z 0-4 R2; R1 je neodvisnofenil, benzil, naftil ali 5- do 10-členski heteroaril, ki vsebuje atome ogljika in 1-4 heteroatome izbrane izmed N, NR11, O, in S; kjer so omenjeni fenil, benzil, naftil in heteroaril vsak substituiran z 0-3 R6; R2, je v vsakem primeru neodvisno izbran izmed: =0, OH, halogena, C-m alkila substituiranega z 0-1 R12, C1-4 alkoksija substituiranega z 0-1 R12, Cm haloalkila, Cm haloalkoksija, in benzila; kadar sta dve skupini R2 vezani na dva različna ogljikova atoma, se lahko združita, da tvorita 1- do 3-členski ogljikov atomski most nad obročem B; kadar sta dve skupini R2 pritrjeni na isti ogljik, lahko skupaj z ogljikovim atomom, na katerega sta vezana, tvorita 3- do 6-členski ogljikov atom, ki vsebuje spiro obroč; R3 je neodvisno izbran izmed: Cu alkila substituiranega z R10, C14 alkoksija substituiranega z R10, Cm haloalkila substituiranega z R10, Cm haloalkoksija substituiranega z R10, OR9, in -0(CH2)i-20(CH2)m R10; R4a je neodvisno izbran izmed: H, halogena, Cm alkila, Cm alkoksija, in -(CH2)m-C3-6 karbocikla; R5, je v vsakem primeru neodvisno izbran izmed: halogena, Cm alkila, Cm haloalkila, Cm alkoksija, in Cm haloalkoksija; R6, je v vsakem primeru neodvisno izbran izmed: halogena, OH, Cm alkiltia, CN, S02(Ci-2 alkila), N(Cm alkila)2, Cm haloalkila, Cm haloalkoksija, Cm alkila substituiranega z 0-1 R7, Cm alkoksija substituiranega z 0-1 R1, -(0)n-(CH2)m-(C3-6 karbocikel substituiran z 0-2 R7), -(CH2)m-(naftil substituiran z 0-2 R7), in -(CH2)m-(5- do 10-členskega heteroarila, ki vsebuje atome ogljika in 1-4 heteroatome izbrane izmed N, O, and S; kjer je omenjeni heteroaril substituiran z 0-2 R7); R7, je v vsakem primeru neodvisno izbran izmed: halogena, OH, Cm alkila, C2-4 alkenila, Cm alkoksija, Cm alkiltia, Cm haloalkila, Cm haloalkoksija, SCF3, CN, NO2, NH2, NH(Ci-4 alkila), N(Cm alkila)2, S02(Ci-2 alkila), in fenila; R9, je v vsakem primeru neodvisno izbran izmed: C1-6 alkila substituiranega z R10, in C1-4 haloalkila substituiranega z R10; R10, je v vsakem primeru neodvisno izbran izmed: CN, C1-4 alkoksija, C1-4 haloalkoksija, C02(Ci-4 alkila), S02(Ci-4 alkila), in tetrazolila; R11, je v vsakem primeru neodvisno izbran izmed: H, C1-4 alkila in benzila; R12, je v vsakem primeru neodvisno izbran izmed: halogena, CN, C1-4 alkila, C1-4 alkoksija, C1-4 haloalkila, C1-4 haloalkoksija, C02(Ci-4 alkila), in tetrazolila; m, je v vsakem primeru neodvisno 0,1, ali 2; in n, je v vsakem primeru neodvisno 0 ali 1.
- 3. Spojina po zahtevku 1 ali 2, kjer: obroč A je neodvisnoobroč B je neodvisno izbran izmed:inR1 je neodvisnofenil substituiran z 0-3 R6 ali heteroaril substituiran z 0-2 R6; kjer je omenjeni heteroaril izbran izmed: furanila, oksazolila, tiazolila, pirazolila, oksadiazolila, piridinila, pirimidinila, pirazinila,R2, je v vsakem primeru neodvisno izbran izmed: OH, halogena, C1-4 alkila substituiranega z 0-1 R12, C-u alkoksija substituiranega z 0-1 R12, in benzila; R3 je neodvisno izbran izmed: C14 alkila substituiranega z 1 R10, Cm alkoksija substituiranega z 1 R10, C1-4 haloalkila substituiranega z 1 R10, OR9, in C1-4 haloalkoksija substituiranega z 1 R10; R4a je neodvisno izbran izmed: H, halogena Cm alkila, C1-4 alkoksija, in C3-6 cikloalkila; R6, je v vsakem primeru neodvisno izbran izmed: halogena, OH, C1-6 alkila substituiranega z 0-1 OH, C1-4 alkoksija, C1-4 alkiltia, C1-4 haloalkila, C1-4 haloalkoksija, CN, S02(Ci-2 alkila), N(Ci-4 alkila>2, C3-6 cikloalkila substituiranega z 0-2 C1-4 alkilom, C5-6 cikloalkenila substituiranega z 0-2 C1-4 alkilom, -O-C3-6 cikloalkilom, benzilom, in oksazolilom; R9, je v vsakem primeru neodvisno izbran izmed: C1-6 alkila substituiranega z R10, in C1-4 haloalkila substituiranega z R10 R10 je v vsakem primeru neodvisno izbran izmed: CN, C1-4 alkoksija, C1-4 haloalkoksija, C02(Ci-4 alkila), S02(Ci-4 alkila), in tetrazolila; in R12, je v vsakem primeru neodvisno izbran izmed: halogena, CN, C1-4 alkila, C1-4 alkoksija, C1-4 haloalkila, C1-4 haloalkoksija, C02(Ci-2 alkila), in tetrazolila.
- 4. Spojina po katerem koli od zahtevkov 1-3, kjer: R1 je neodvisnofenil substituiran z 0-3 R6, ali heteroaril substituiran z 0-2 R6; kjer je omenjeni heteroaril izbran izmed: tiazolila, piridinila, pirimidinila, pirazinila,
- 5. Spojina po katerem koli od zahtevkov 1-4, kjer: Obroč B neodvisno izbran izmed:R1 je neodvisno fenil substituiran z 0-3 R6, piridinil substituiran z 0-2 R6, pirazinil substituiran z 0-2 R6, pirimidinil substituiran z 0-2 R6, tiazolil substituiran z 0-2 R6, inR2, je v vsakem primeru, neodvisno izbran izmed: OH, halogena, Cm alkila substituiranega z 0-1 CN, C1-4 alkoksija, benzila, in tetrazolilmetila.
- 6. Spojina po katerem koli od zahtevkov 1-5, kjer: obroč B je neodvisno izbran izmed:R1, je v vsakem primeru, neodvisno fenil substituiran z 0-3 R6 ali piridinil substituiran z 0-2 R6; R2, je v vsakem primeru, neodvisno izbran izmed: halogena, Cm alkila, Cm alkoksija in tetrazolilmetila; R3, je v vsakem primeru, neodvisno izbran izmed: Cm alkila substituiranega z R10, Cm alkoksija substituiranega z R10, OR9, in -0(CH2)i-20(CH2)mR1°; R6, je v vsakem primeru, neodvisno izbran izmed: halogena, Ci-β alkila, Ci-4 alkoksija, Cm haloalkila, Cm haloalkoksija, C3-6 cikloalkila substituiranega z 0-2 Cm alkila, C5-6 cikloalkenila substituiranega z 0-2 C1-4 alkila, in benzila; R9, je v vsakem primeru, neodvisno izbran izmed: C1.6 alkila substituiranega R10, in Cm haloalkila substitiranega z R10; in R10, je v vsakem primeru, neodvisno izbran izmed: CN, Cm alkoksija, Cm haloalkoksija, C02(Cm alkila), S02(Cm alkila), in tetrazolila.
- 7. Spojina po zahtevku 1, ki ima formulo (lil), (lila), (lllb) ali (lile):ali njena stereoizomera, tavtomera, farmacevtsko sprejemljiva sol, polimorf ali solvat, kjer: R1, je v vsakem primeru, neodvisno fenil substituiran z 0-3 R6 ali piridinil substituiran z 0-2 R6; R2, je v vsakem primeru, neodvisno izbran izmed: halogena, Cm alkila, in Ci-4 alkoksija; R3, je v vsakem primeru, neodvisno izbran izmed: Cm alkila substituiranega z C1-4 alkoksijem, in C1-4 alkoksija substituiranega z C1-4 alkoksijem; R4a, je v vsakem primeru, neodvisno izbran izmed: H, halogena, Cm alkila, C1-4 alkoksija, in ciklopropila; R5 je v vsakem primeru, neodvisno izbran izmed: halogena, Cm haloalkila, in C1-6 alkoksija; in R6, je v vsakem primeru, neodvisno izbran izmed: halogena, C1-6 alkila, C1-4 alkoksija, C3-6 cikloalkila substituiranega z 0-2 Cm alkila, in C5-6 cikloalkenila substituiranega z 0-2 Cm alkila.
- 8. Spojina po zahtevku 7, kjer: R\ je v vsakem primeru, neodvisno fenil substituiran z 0-3 R6 ali piridinil substituiran z 0-2 R6; R2 je v vsakem primeru, neodvisno izbran izmed: halogena in C1-2 alkila; R3, je v vsakem primeru, neodvisno izbran izmed: C1-4 alkila substituiranega z C1-4 alkoksijem, in C1-4 alkoksi substituiran z C1-4 alkoksijem; R4a, je v vsakem primeru, neodvisno izbran izmed: H in metila; R5, je v vsakem primeru, neodvisno izbran izmed: halogena, C1-4 haloalkila, in C1-6 alkoksija; in R6, je v vsakem primeru, neodvisno izbran izmed: halogena, C1-6 alkila, in C1-4 alkoksija.
- 9. Spojina po zahtevku 1, ki je izbrana izmedali njena stereoizomera, tavtomera, farmacevtsko sprejemljiva sol, polimorf ali solvat.
- 10. Spojina po zahtevku 1, ki je izbrana izmedali njena stereoizomera, tavtomera, farmacevtsko sprejemljiva sol, polimorf ali solvat.
- 11. Farmacevtski sestavek, ki obsega farmacevtsko sprejemljiv nosilec in spojino po katerem koli od zahtevkov 1-10 in po izbiri nadalje vsebuje eno ali več drugih primernih terapevtskih sredstev, izbranih izmed: anti-diabetičnih sredstev, anti-hiperglikemičnih sredstev, anti-hiperinsulinemičnih sredstev, anti-retinopatskih sredstev, anti-neuropatskih sredstev, anti-nefropatskih sredstev, antiatherosklerotičnih sredstev, anti-ishemičnih sredstev, anti-hipertenzivnih sredstev, sredstev proti debelosti, anti-disilipidemskih sredstev, anti-hiperlipidemičnih sredstev, anti-hipertrigliceridemskih sredstev, anti-hiperholesterolemičnih sredstev, anti-restenotičnih sredstev, sredstev proti pankreasu, sredstev za zniževanje lipidov, anorektičnih sredstev in sredstev za zatiranje apetita.
- 12. Farmacevtski sestavek po zahtevku 11, ki nadalje obsega inhibitor dipeptidil peptidaze-IV in/ali inhibitor natrijevega glukoznega transporterja-2.
- 13. Spojina po katerem koli od zahtevkov 1-10, za uporabo pri terapiji.
- 14. Spojina po katerem koli od zahtevkov 1 do 10 za uporabo pri zdravljenju sladkorne bolezni, hiperglikemije, okvare na toleranco glukoze, gestacijskega diabetesa, insulinske rezistence, hiperinsulinemije, retinopatije, nevropatije, nefropatije, diabetične bolezni ledvic, akutne poškodbe ledvic, kardiorenalnega sindroma, akutnega koronarnega sindroma, zakasnjenega celjenja ran, ateroskleroze in njenih posledic, nenormalnega delovanja srca, kongestivnega srčnega popuščanja, ishemičnega miokarda, možganske kapi, metaboličnega sindroma, hipertenzije, debelosti, bolezni zamaščenih jeter, dislipidemije, dislipidemije, hiperlipidemija, hipertrigliceridemije, hiperholesterolemije, (LDL), ne-srčne ishemije, pankreatitisa, lipidnih motenj in bolezni jeter, kot so NASH (nealkoholni steathepatitis), NAFLD (bolezen brezalkoholnih zamaščenih jeter), jetrne ciroze , vnetnih črevesnih bolezni, ki vključujejo ulcerozni kolitis in Crohnovo bolezen, celiakije, osteoartritisa, nefritisa, psoriaze, atopijskega dermatitisa in vnetja kože.
- 15. Spojina za uporabo po zahtevku 13 ali zahtevku 14, kjer se spojina po katerem koli od zahtevkov 1-10 uporablja istočasno, ločeno ali zaporedno z enim ali večimi dodatnimi terapevtskimi sredstvi.
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