HRP20151163T1 - Antagonisti trpm8 receptora - Google Patents

Antagonisti trpm8 receptora Download PDF

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HRP20151163T1
HRP20151163T1 HRP20151163TT HRP20151163T HRP20151163T1 HR P20151163 T1 HRP20151163 T1 HR P20151163T1 HR P20151163T T HRP20151163T T HR P20151163TT HR P20151163 T HRP20151163 T HR P20151163T HR P20151163 T1 HRP20151163 T1 HR P20151163T1
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Croatia
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chloronaphthalen
methyl
oxy
ylmethyl
amine
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HRP20151163TT
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Alessio Moriconi
Gianluca Bianchini
Laura Brandolini
Andrea Aramini
Chiara Liberati
Silvia Bovolenta
Andrea Beccari
Simone Lorenzi
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Dompé farmaceutici s.p.a.
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Publication of HRP20151163T1 publication Critical patent/HRP20151163T1/hr

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Claims (12)

1. Tvari koje imaju formulu (I): [image] i njihove farmaceutski prihvatljive soli, pri čemu: R je odabran između: H, Br, CN, NO2, SO2NH2, SO2NHR' i SO2N(R')2, gdje je R' odabran između linearnog ili razgranatog C1-C4 alkila; X je odabran između: F, Cl, C1-C3 alkila, NH2 i OH Y je odabran između: -O-, CH2, NH i SO2 R1 i R2, nezavisno jedan od drugoga, odabrani su između H, F i linearnog ili razgranatog C1-C4 alkila; R3 i R4, nezavisno jedan od drugoga, odabrani su između H i linearnog ili razgranatog C1-C4 alkila; Z je odabran između: NR6 i R6R7N+, gdje su R6 i R7, nezavisno jedan od drugoga, odabrani između: H i linearnog ili razgranatog C1-C4 alkila R5 je ostatak odabran između: H i linearnog ili razgranatog C1-C4 alkila Het je heteroarilna grupa odabrana između pirolila, N-metilpirolila, tiofenila, furila i piridinila, nesupstituirana ili supstituirana s jednim ili više supstituenata odabranih između F, Cl, CH3, NH2 i OH.
2. Tvari u skladu s patentnim zahtjevom 1, pri čemu, nezavisno jedan od drugoga: R je odabran između H, Br i CN. X je odabran između F, Cl i C1-C3 alkila; Y je odabran između -O-, CH2, NH i SO2, R1 i R2, nezavisno jedan od drugoga, odabrani su između H, F i CH3; R3 i R4, nezavisno jedan od drugoga, odabrani su između H i CH3; Z je odabran između NR6 i R6R7N+ gdje su R6 i R7, nezavisno jedan od drugoga, odabrani između H i CH3; R5 je odabran između H i CH3;
3. Tvari u skladu s patentnim zahtjevom 1 ili 2, pri čemu, nezavisno jedan od drugoga, R je odabran između H i CN; X je odabran između F i Cl; Y je odabran između CH2, O i SO2; Z je odabran između NH i N+( CH3)2; R5 je H, Het je supstituiran s barem jednim supstituentom odabranim između F, Cl i CH3.
4. Tvari u skladu s bilo kojim od patentnih zahtjeva 1 do 3, pri čemu je Het 5-supstituirani pirol-2-il, 5-supstituirani N-metilpirol-2-il, 5- supstituirani tiofen-2-il ili 5- supstituirani fur-2-il.
5. Tvari u skladu s bilo kojim od patentnih zahtjeva 1 do 4 odabrane iz grupe koja se sastoji od: 2-[(1-kloronaftalen-2-il)oksi]-N-(furan-2-ilmetil)etanaminij klorid (1) 2-[(1-kloronaftalen-2-il)oksi]-N-[(5-metilfuran-2-il)metil]etanaminij klorid (2) N-[(5-klorofuran-2-il)metil]-2-[(1-kloronaftalen-2-il)oksi]etanaminij (3) 2-[(1-kloronaftalen-2-il)oksi]-N-[(5-klorotiofen-2-il)metil]etanaminij (4) 2-[(1-kloronaftalen-2-il)oksi]-N-(tiofen-2-ilmetil)etanaminij (5) 2-[(1-kloronaftalen-2-il)oksi]-N-(piridin-2-ilmetil)etanaminij (6) 2-[(1-kloronaftalen-2-il)oksi]-N-[(1-metil-1H-pirol-2-il)metil]etanaminij (7) 1-[(1-kloronaftalen-2-il)oksi]-N-(furan-2-ilmetil)-2-metilpropan-2-amin (8) 1-[(1-kloronaftalen-2-il)oksi]-2-metil-N-[(5-metilfuran-2-il)metil]propan-2-amin (9) N-[(5-klorofuran-2-il)metil]-1-[(1-kloronaftalen-2-il)oksi]-2-metilpropan-2-amin (10) 1-[(1-kloronaftalen-2-il)oksi]-N-[(5-klorotiofen-2-il)metil]-2-metilpropan-2-amin (11) 1-[(1-kloronaftalen-2-il)oksi]-2-metil-N-(tiofen-2-ilmetil)propan-2-amin (12) 1-[(1-kloronaftalen-2-il)oksi]-2-metil-N-(piridin-2-ilmetil)propan-2-amin (13) 1-[(1-kloronaftalen-2-il)oksi]-2-metil-N-[(1-metil-1H-pirol-2-il)metil]propan-2-amin (14) 2-[(1-kloronaftalen-2-il)oksi]-N-(furan-2-ilmetil)propan-1-amin (15) 2-[(1-kloronaftalen-2-il)oksi]-N-[(5-metilfuran-2-il)metil]propan-1-amin (16) N-[(5-klorofuran-2-il)metil]-2-[(1-kloronaftalen-2-il)oksi]propan-1-amin (17) 2-[(1-kloronaftalen-2-il)oksi]-N-[(5-klorotiofen-2-il)metil]propan-1-amin (18) 2-[(1-kloronaftalen-2-il)oksi]-N-(tiofen-2-ilmetil)propan-1-amin (19) 1-[(1-kloronaftalen-2-il)oksi]-N-(furan-2-ilmetil)propan-2-amin (20) 1-[(1-kloronaftalen-2-il)oksi]-N-[(5-metilfuran-2-il)metil]propan-2-amin (21) N-[(5-klorofuran-2-il)metil]-1-[(1-kloronaftalen-2-il)oksi]propan-2-amin (22) 1-[(1-kloronaftalen-2-il)oksi]-N-[(5-klorotiofen-2-il)metil]propan-2-amin (23). 1-[(1-kloronaftalen-2-il)oksi]-N-(tiofen-2-ilmetil)propan-2-amin (24) 2-[(1-kloronaftalen-2-il)sulfonil]-N-(furan-2-ilmetil)etanamin (25) 2-[(1-kloronaftalen-2-il)sulfonil]-N-[(5-metilfuran-2-il)metil]etanamin (26) N-[(5-klorofuran-2-il)metil]-2-[(1-kloronaftalen-2-il)sulfonil]etanamin (27) 2-[(1-kloronaftalen-2-il)sulfonil]-N-[(5-klorotiofen-2-il)metil]etanamin (28) 2-[(1-kloronaftalen-2-il)sulfonil]-N-(tiofen-2-ilmetil)etanamin (29) 2-[(1-kloronaftalen-2-il)sulfonil]-N-(piridin-2-ilmetil)etanamin (30) 2-[(1-kloronaftalen-2-il)sulfonil]-N-[(1-metil-1H-pirol-2-il)metil] etanamin (31) 3-(1-kloronaftalen-2-il)-N-(furan-2-ilmetil)propan-1-amin (32) 3-(1-kloronaftalen-2-il)-N-[(5-metilfuran-2-il)metil]propan-1-amin (33) N-[(5-klorofuran-2-il)metil]-3-(1-kloronaftalen-2-il)propan-1-amin (34) 3-(1-kloronaftalen-2-il)-N-[(5-klorotiofen-2-il)metil]propan-1-amin (35) 3-(1-kloronaftalen-2-il)-N-(tiofen-2-ilmetil)propan-1-amin (36) 3-(1-kloronaftalen-2-il)-N-(piridin-2-ilmetil)propan-1-amin (37) 2-[(1-kloronaftalen-2-il)oksi]-N-(furan-2-ilmetil)-N-metiletanamin (38) 2-[(1-kloronaftalen-2-il)oksi]-N-(furan-2-ilmetil)-N,N-dimetiletanaminij jodid (39) N-{2-[(1-kloronaftalen-2-il)oksi]etil}-1-(5-metilfuran-2-il)etanamin (40) N-(1-kloronaftalen-2-il)-N’-(furan-2-ilmetil)etan-1,2-diamin (41) N-(1-kloronaftalen-2-il)-N’-[(5-metilfuran-2-il)metil]etan-1,2-diamin (42) N-[(5-klorofuran-2-il)metil]-N’-(1-kloronaftalen-2-il)etan-1,2-diamin (43) N-(1-kloronaftalen-2-il)-N’-[(5-klorotiofen-2-il)metil]etan-1,2-diamin (44) N-(1-kloronaftalen-2-il)-N’-(tiofen-2-ilmetil)etan-1,2-diamin (45) N-(1-kloronaftalen-2-il)-N’-(piridin-2-ilmetil)etan-1,2-diamin (46) N-(1-kloronaftalen-2-il)-N’-[(1-metil-1H-pirol-2-il)metil]etan-1,2-diamin (47) 2-[(1-fluoronaftalen-2-il)oksi]-N-(furan-2-ilmetil)etanamin (48) 2-[(1-fluoronaftalen-2-il)oksi]-N-[(5-metilfuran-2-il)metil]etanamin (49) N-[(5-klorofuran-2-il)metil]-2-[(1-fluoronaftalen-2-il)oksi]etanamin (50) N-[(5-klorotiofen-2-il)metil]-2-[(1-fluoronaftalen-2-il)oksi]etanamin (51) 2-[(1-fluoronaftalen-2-il)oksi]-N-(tiofen-2-ilmetil)etanamin (52) 2-[(1-fluoronaftalen-2-il)oksi]-N-(piridin-2-ilmetil)etanamin (53) 2-[(1-fluoronaftalen-2-il)oksi]-N-[(1-metil-1H-pirol-2-il)metil]etanamin (54) 5-kloro-6-{2-[(piridin-2-ilmetil)amino]etoksi}naftalen-2-karbonitril (55) 5-kloro-6-{2-[(furan-2-ilmetil)amino]etoksi}naftalene-2-karbonitril (56) 5-kloro-6-(2-{[(5-metilfuran-2-il)metil]amino}etoksi)naftalen-2-karbonitril (57) 5-kloro-6-(2-{[(5-klorofuran-2-il)metil]amino}etoksi)naftalen-2-karbonitril (58) 5-kloro-6-(2-{[(5-klorotiofen-2-il)metil]amino}etoksi)naftalen-2-karbonitril (59) 5-kloro-6-{2-[(tiofen-2-ilmetil)amino]etoksi}naftalen-2-karbonitril (60). 2-[(1-etilnaftalen-2-il)oksi]-N-(furan-2-ilmetil)etanamin (61) 2,2-difluoro-2-[(1-fluoronaftalen-2-il)oksi]-N-(furan-2-ilmetil)etanamin (62) 2-[(6-bromo-1-fluoronaftalen-2-il)oksi]-N-(furan-2-ilmetil)etanamin (63)
6. Tvari u skladu s bil kojim od patentnih zahtjeva 1 do 5, odabrane iz grupe koja se sastoji od: 2-[(1-kloronaftalen-2-il)oksi]-N-(furan-2-ilmetil)etanaminij klorid (1) 2-[(1-kloronaftalen-2-il)oksi]-N-(tiofen-2-ilmetil)etanaminij (5) 2-[(1-kloronaftalen-2-il)oksi]-N-(piridin-2-ilmetil)etanaminij (6) 1-[(1-kloronaftalen-2-il)oksi]-N-(furan-2-ilmetil)-2-metilpropan-2-amin (8) 1-[(1-kloronaftalen-2-il)oksi]-2-metil-N-(piridin-2-ilmetil)propan-2-amin (13) 1-[(1-kloronaftalen-2-il)oksi]-2-metil-N-[(1-metil-1H-pirol-2-il)metil]propan-2-amin (14) 2-[(1-kloronaftalen-2-il)sulfonil]-N-(furan-2-ilmetil)etanamin (25) 3-(1-kloronaftalen-2-il)-N-(furan-2-ilmetil)propan-1-amin (32) 3-(1-kloronaftalen-2-il)-N-[(5-metilfuran-2-il)metil]propan-1-amin (33) N-[(5-klorofuran-2-il)metil]-3-(1-kloronaftalen-2-il)propan-1-amin (34) 3-(1-kloronaftalen-2-il)-N-[(5-klorotiofen-2-il)metil]propan-1-amin (35) 2-[(1-fluoronaftalen-2-il)oksi]-N-(furan-2-ilmetil)etanamin (48) 2-[(1-fluoronaftalen-2-il)oksi]-N-(tiofen-2-ilmetil)etanamin (52) 2-[(1-fluoronaftalen-2-il)oksi]-N-(piridin-2-ilmetil)etanamin (53) 5-kloro-6-{2-[(piridin-2-ilmetil)amino]etoksi}naftalen-2-karbonitril (55) 5-kloro-6-{2-[(tiofen-2-ilmetil)amino]etoksi}naftalen-2-karbonitril (60).
7. Tvari u skladu s bilo kojim od patentnih zahtjeva 1 do 6, za uporabu u prevenciji i/ili liječenju poremećaja i/ili bolesti povezanih s aktivnosti TRPM8 (prijelazni receptor potencijalnog kationskog kanala iz podobitelji M član 8, engl. Transient Receptor Potential cation channel subfamily M member 8), pri čemu su navedeni poremećaji i/ili bolesti odabrani iz grupe koja se sastoji od: upalnih stanja, ishemije, boli, uroloških poremećaja, moždanog udara, psihijatrijskih poremećaja i neurodegeneracije.
8. Tvari za uporabu u skladu s patentnim zahtjevom 7, pri čemu su navedeni poremećaj i/ili bolesti odabrani između kronične boli, neuropatske boli uključujući hladnu alodiniju i dijabetičku neuropatske boli, postoperativne boli, osteoartritičke boli, boli kod reumatoidnog artritisa, boli kod karcinoma, neuralgije, fibromijalgije, neuropatija, algezije, ozljede živca, migrena, glavobolja, svrbeži, sindroma iritabilnog crijeva i respiratornih bolesti, sindroma mjehura, intersticijskog cistitisa, pretjerane aktivnosti detruzora (preaktivnog mjehura), urinarne inkontinencije, neurogene pretjerane aktivnosti detruzora (hiperrefleksije detruzora), idiopatske pretjerane aktivnosti detruzora (nestabilnosti detruzora), benigne hiperplazije prostate, poremećaja donjih mokraćnih puteva i simptoma donjih mokraćnih puteva, tjeskobe i depresije
9. Farmaceutski sastav obuhvaća kao aktivni sastojak barem jednu tvar u skladu s bilo kojim od patentnih zahtjeva 1 do 8 u kombinaciji s odgovarajućim ekscipijensima i/ili diluentima.
10. Farmaceutski sastav u skladu s patentnim zahtjevom 9, pogodan za davanje intravezikalno, intravenski, dermalno, oralno i inhaliranjem.
11. Farmaceutski sastav u skladu s patentnim zahtjevom 9 ili 10, u obliku formulacije s kontroliranim otpuštanjem.
12. Postupak za pripravu tvari u skladu s bilo kojim od patentnih zahtjeva 1 do 8, obuhvaća sljedeće korake: reagiranje aminskog intermedijera IA: [image] pri čemu X, R1, R2, R3, R4 i Z imaju ista značenja kao u formuli (I) i Y'=O, CH2, NH i S, s R5CO-Het, pri čemu Het i R5 imaju ista značenja kao u formuli (I), i dodavanje slijedom u reakcijsku smjesu blagog reducirajućeg agensa, poželjno natrij bor hidrida, time dobivajući tvar (IB) [image] koja se podudara s konačnom tvari formule (I) u slučaju Y'=O, CH2, NH, a u slučaju Y'=S navedeni postupak nadalje uključuje sljedeći korak: oksidiranje tvari (IB) za dobivanje tvari formule (I) koja ima Y=SO2.
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