HRP20190819T1 - Derivati 2-aril-4-hidroksi-1,3-tiazola koji su korisni kao inhibitori trpm8 u liječenju neuralgije, bola, kopb i astme - Google Patents

Derivati 2-aril-4-hidroksi-1,3-tiazola koji su korisni kao inhibitori trpm8 u liječenju neuralgije, bola, kopb i astme Download PDF

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HRP20190819T1
HRP20190819T1 HRP20190819TT HRP20190819T HRP20190819T1 HR P20190819 T1 HRP20190819 T1 HR P20190819T1 HR P20190819T T HRP20190819T T HR P20190819TT HR P20190819 T HRP20190819 T HR P20190819T HR P20190819 T1 HRP20190819 T1 HR P20190819T1
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compound
hydroxy
thiazol
propan
fluorophenyl
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Andrea Aramini
Gianluca Bianchini
Laura Brandolini
Andrea Beccari
Samuele Lillini
Giuseppe Nano
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Dompé Farmaceutici S.P.A.
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Claims (16)

1. Spoj s formulom (I): naznačen time što X je kisik, sumpor, NH, NOH ili NOMe; R je skupina odabrana od arila i heteroarila, po izboru supstituirana s jednim ili više supstituenata odabranih od - vodika, - halogena, - CF3, - ravnog ili razgranatog C1-C6 alkila, - OR5 i - NR6R7, pri čemu R5, R6 i R7 su neovisno vodik ili ravni ili razgranati C1-C6 alkil; R1 je skupina odabrana od - ravnog ili razgranatog C1-C6 alkila, - (CH2)m-OR2, pri čemu m je cijeli broj između 1 i 3 i R2 je odabran od vodika i ravnog C1-C3 alkila, - C3-C6 cikloalkila i - N(R3)OR4, pri čemu R3 i R4 su neovisno vodik ili ravni ili razgranati C1-C3 alkil, i njihove farmaceutski prihvatljive soli, za uporabu kao lijek.
2. Spoj za uporabu prema zahtjevu 1, naznačen time što X je kisik.
3. Spoj za uporabu prema zahtjevu 1 ili 2, naznačen time što R je fenil ili 5- ili 6-eročlani heteroaril koji sadržava od 1 do 3 heteroatoma koji su odabrani od N, O i S, poželjno, navedeni 5- ili 6-eročlani heteroaril je odabran iz skupine koja sadrži tiofenil, furanil, pirolil, imidazolil, pirazolil, oksadiazolil, oksazolil i piridinil.
4. Spoj za uporabu prema zahtjevima 1 do 3, naznačen time što R je aril po izboru supstituiran sa skupinom odabranom od: - halogena, poželjno odabranog od Br i F, - ravnog ili razgranatog C1-C3 alkila, poželjno CH3, - OR5 i NR6R7, pri čemu su R5, R6 i R7 neovisno vodik ili ravni C1-C3 alkil, poželjno OH, NH2 ili NHCH3, redom.
5. Spoj za uporabu prema zahtjevima 1 do 4, naznačen time što R je heteroaril i heteroaril je po izboru supstituiran s ravnim ili razgranatim C1-C6 alkilom, poželjno s CH3.
6. Spoj za uporabu prema zahtjevima 1 do 5, naznačen time što R je odabran iz skupine koja sadrži 3-fluorofenil, 4-fluorofenil, 2-bromofenil, 3-bromofenil, 2-metilfenil, 3-metilfenil, 4-metilfenil, 2-hidroksifenil, 3-hidroksifenil, 4-hidroksifenil, 3-aminofenil, 4-aminofenil, 3-metilaminofenil, 4-metilaminofenil, tiofen-2il, furan-2il, pirol-2il, 1H-imidazol-5il, 1-metil-imidazol-5il, pirazol-4il, 1,2,4-oksadiazol-3il, 1,2-oksazol-5il, piridin-2il, piridin-3il i piridin-4il.
7. Spoj za uporabu prema zahtjevima 1 do 6, naznačen time što R1 je - ravni ili razgranati C1-C6 alkil, - (CH2)m-OR2 pri čemu m je 1 i R2 je ravni C1-C3 alkil, - C3-C6 cikloalkil ili - N(R3)OR4, pri čemu R3 i R4 su kako je definirano u zahtjevu 1.
8. Spoj za uporabu prema zahtjevima 1 do 7, naznačen time što R1 je - ravni ili razgranati C1-C6 alkil, - (CH2)m-OR2 pri čemu m je 1 i R2 je CH3, - ciklopropil - ili - N(R3)OR4, pri čemu R3 i R4 su neovisno C1-C3 alkil, poželjno CH3.
9. Spoj za uporabu prema zahtjevima 1 do 8, naznačen time što R1 je odabran iz skupine koja sadrži: metil, etil, izopropil, izobutil, CH2OCH3, ciklopropil ili -N(CH3)OCH3.
10. Spoj s formulom (I): naznačen time što X je kisik, sumpor, NH, NOH, ili NOMe; R je skupina odabrana od arila i heteroarila, po izboru supstituirana s jednim ili više supstituenata odabranih od - vodika, - halogena, - CF3, - ravnog ili razgranatog C1-C6 alkila, - OR5 i - NR6R7, pri čemu R5, R6 i R7 su neovisno vodik ili ravni ili razgranati C1-C6 alkil; R1 je skupina odabrana od - ravnog ili razgranatog C1-C6 alkila, - (CH2)m-OR2, pri čemu m je cijeli broj između 1 i 3 i R2 je odabran od vodika i ravnog C1-C3 alkila, - C3-C6cikloalkila i - N(R3)OR4, pri čemu R3 i R4 su neovisno vodik ili ravni ili razgranati C1-C3 alkil, i njihove farmaceutski prihvatljive soli, uz uvjet da kada R1 je metil, R nije odabran iz niza koji čine 3-piridil, 4-klorofenil, 4-trifluorometilfenil, 3-tiofenil, 3-tiazolil-(2-metil), fenil, tiazol, 2-4-difluorofenil, 4-metoksifenil i 2-metiltiazol, dalje pod uvjetom da je isključen 1-[4-hidroksi-2-(tiofen-2-il)-1,3-tiazol-5-il]etanon.
11. Spoj prema zahtjevu 10, naznačen time što je R1 različit od metila.
12. Spoj prema zahtjevu 10, naznačen time što je odabran iz skupa koji čine: 1-[2-(3-fluorofenil)4-hidroksi-1,3-tiazol-5-il]propan-1-on (spoj br. 1) natrij 2-(3-fluorofenil)-5-propanoil-1,3-tiazol-4-olat (spoj br. 2) 2-(3-fluorofenil)-4-hidroksi-N-metoksi-N-metil-1,3-tiazol-5-karboksamid (spoj br. 3) 1-(2-(3-fluorofenil)-4-hidroksitiazol-5-il)etanon (spoj br. 4) 1-[2-(3-fluorofenil)-4-hidroksi-1,3-tiazol-5-il]-2-metilpropan-1-on (spoj br. 5) 4-hidroksi-N-metoksi-N-metil-2-(tiofen-2-il)-1,3-tiazol-5-karboksamid (spoj br.6) 1-[4-hidroksi-2-(tiofen-2-il)-1,3-tiazol-5-il]propan-1-on (spoj br. 7) 4-hidroksi-N-metoksi-N-metil-2-(2-metilfenil)-1,3-tiazol-5-karboksamid(spoj br. 8) 1-[4-hidroksi-2-(2-metilfenil)-1,3-tiazol-5-il]propan-1-on (spoj br.9) 2-(2-bromofenil)-4-hidroksi-N-metoksi-N-metil-1,3-tiazol-5-karboksamid (spoj br.10) 1-[2-(2-bromofenil)-4-hidroksi-1,3-tiazol-5-il]propan-1-on (spoj br. 11) 4-hidroksi-2-(2-hidroksifenil)-N-metoksi-N-metil-1,3-tiazol-5-karboksamid (spoj br. 12) 1-[2-(2-hidroksifenil)-4-hidroksi-1,3-tiazol-5-il]propan-1-on (spoj br. 13) 1-[2-(3-bromofenil)-4-hidroksi-1,3-tiazol-5-il]propan-1-on (spoj br. 14) 1-[2-(furan-2-il)-4-hidroksi-1,3-tiazol-5-il]propan-1-on (spoj br. 15) 1-[4-hidroksi-2-(1H-pirol-2-il)-1,3-tiazol-5-il]propan-1-on (spoj br. 16) 1-[4-hidroksi-2-(1-metil-1H-pirol-2-il)-1,3-tiazol-5-il]propan-1-on (spoj br. 17) 1-[4-hidroksi-2-(1-metil-1H-imidazol-5-il)-1,3-tiazol-5-il]propan-1-on (spoj br. 18) 1-[4-hidroksi-2-(1H-imidazol-5-il)-1,3-tiazol-5-il]propan-1-on (spoj br. 19) 1-[4-hidroksi-2-(1-metil-1H-pirazol-4-il)-1,3-tiazol-5-il]propan-1-on (spoj br. 20) 1-[4-hidroksi-2-(tiofen-2-il)-1,3-tiazol-5-il]butan-1-on (spoj br. 21) 1-[4-hidroksi-2-(tiofen-2-il)-1,3-tiazol-5-il]-3-metilbutan-1-on (spoj br. 22) 1-[4-hidroksi-2-(1,2,4-oksadiazol-3-il)-1,3-tiazol-5-il]propan-1-on (spoj br. 23) 1-[4-hidroksi-2-(1,2-oksazol-5-il)-1,3-tiazol-5-il]propan-1-on (spoj br. 24) 1-[4-hidroksi-2-(piridin-3-il)-1,3-tiazol-5-il]propan-1-on (spoj br. 25) 1-[4-hidroksi-2-(piridin-4-il)-1,3-tiazol-5-il]propan-1-on (spoj br. 26) 1-[4-hidroksi-2-(piridin-2-il)-1,3-tiazol-5-il]propan-1-on (spoj br. 27) 1-[4-hidroksi-2-(3-hidroksifenil)-1,3-tiazol-5-il]propan-1-on (spoj br. 28) 1-[4-hidroksi-2-(4-hidroksifenil)-1,3-tiazol-5-il]propan-1-on (spoj br. 29) 1-[4-hidroksi-2-(3-metilfenil)-1,3-tiazol-5-il]propan-1-on (spoj br. 30) 1-[4-hidroksi-2-(4-metilfenil)-1,3-tiazol-5-il]propan-1-on (spoj br. 31) 1-[2-(3-aminofenil)-4-hidroksi-1,3-tiazol-5-il]propan-1-on (spoj br. 32) 1-[2-(4-aminofenil)-4-hidroksi-1,3-tiazol-5-il]propan-1-on (spoj br. 33) 1-{4-hidroksi-2-[3-(metilamino)fenil]-1,3-tiazol-5-il}propan-1-on (spoj br. 34) 1-{4-hidroksi-2-[4-(metilamino)fenil]-1,3-tiazol-5-il}propan-1 -on (spoj br. 35) 1-[2-(4-fluorofenil)-4-hidroksi-1,3-tiazol-5-il]propan-1-on (spoj br. 36) 1-[2-(3-fluorofenil)-4-hidroksi-1,3-tiazol-5-il]butan-1-on (spoj br. 37) 1-[2-(3-fluorofenil)-4-hidroksi-1,3-tiazol-5-il]-3-metilbutan-1-on (spoj br. 38) 1-[2-(3-fluorofenil)-4-hidroksi-1,3-tiazol-5-il]-2-metoksietanon (spoj br. 39) 1-[2-(3-fluorofenil)-4-hidroksi-1,3-tiazol-5-il]propan-1-tion (spoj br. 40) 2-(3-fluorofenil)-4-hidroksi-N-metoksi-N-metil-1,3-tiazol-5-karbotioamid (spoj br. 41) 2-(3-fluorofenil)-5-[(1E)-N-metoksipropanimidoil]-1,3-tiazol-4-ol (spoj br. 42) 2-(3-fluorofenil)-5-propanimidoil-1,3-tiazol-4-ol (spoj br.43) i 2-(3-fluorofenil)-5-[(1E)-N-hidroksipropanimidoil]-1,3-tiazol-4-ol (spoj br.44).
13. Spoj prema zahtjevu 12, naznačen time što je odabran iz skupa koji čine: natrij 2-(3-fluorofenil)-5-propanoil-1,3-tiazol-4-olat (spoj br. 2) 2-(3-fluorofenil)-4-hidroksi-N-metoksi-N-metil-1,3-tiazol-5-karboksamid (spoj br. 3) 4-hidroksi-2-(2-hidroksifenil)-N-metoksi-N-metil-1,3-tiazol-5-karboksamid (spoj br. 12) i 1-[4-hidroksi-2-(3-hidroksifenil)-1,3-tiazol-5-il]propan-1-on (spoj br. 28).
14. Spoj kako je definiran u bilo kojem od patentnih zahtjeva 1 do 13, naznačen time što je namijenjen upotrebi za prevenciju i/ili liječenje bolesti odabrane iz skupine koju čine svrbež, iritabilne bolesti crijeva, prehladom izazvani i/ili pogoršani respiratorni poremećaji, ishemija, bol, urološki poremećaji, moždani udar, psihijatrijski poremećaji i neurodegeneracija.
15. Spoj za uporabu kao prema zahtjevu 14, naznačen time što je navedena bolest odabrana od kronične boli, neuropatske boli, postoperativne boli, boli zbog raka, osteoartritične boli, reumatoidne artritične boli, neuralgije, fibromialgije, neuropatija, fibromialgije, algezije, ozljede živca, migrene, glavobolje, svrbeža, iritabilne bolesti crijeva, sindroma bolnog mokraćnog mjehura, intersticijskog cistitisa, prekomjerne aktivnosti detruzora, urinarne inkontinencije, neurogene prekomjerne aktivnosti detruzora, idiopatske prekomjerne aktivnosti detruzora, benigne hiperplazije prostate, poremećaja donjeg mokraćnog sustava i simptoma donjeg mokraćnog sustava, anksioznosti, depresije i prehladom izazvane /ili pogoršane plućne hipertenzije, KOPB i astme.
16. Farmaceutski pripravak naznačen time što kao aktivni sastojak sadrži barem jedan spoj kao što je definiran u bilo kojem od zahtjeva 1 do 13 u kombinaciji s farmaceutski prihvatljivim ekscipijentima i/ili sredstvima za razrjeđivanje.
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