HRP20170361T1 - Spojevi pirazola kao inhibitori sigma receptora - Google Patents

Spojevi pirazola kao inhibitori sigma receptora Download PDF

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HRP20170361T1
HRP20170361T1 HRP20170361TT HRP20170361T HRP20170361T1 HR P20170361 T1 HRP20170361 T1 HR P20170361T1 HR P20170361T T HRP20170361T T HR P20170361TT HR P20170361 T HRP20170361 T HR P20170361T HR P20170361 T1 HRP20170361 T1 HR P20170361T1
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pyrazol
methoxy
methyl
compound
ethyl
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HRP20170361TT
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Mónica GARCÍA LÓPEZ
Antoni Torrens Jover
José Luis Díaz Fernández
Ana María Caamaño Moure
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Laboratorios Del Dr. Esteve, S.A.
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Claims (12)

1. Spoj opće formule (I): [image] , naznačen time što R1 predstavlja supstituirani ili nesupstituirani, aromatski ili nearomatski heterociklil, gdje je heterociklil stabilni 3- do 15-eročlani prstenasti radikal, koji se sastoji od atoma ugljika i od jednog do pet heteroatoma, koje se bira iz skupine koju čine dušik, kisik, te sumpor; supstituirani ili nesupstituirani aril, gdje je aril skupina koja sadrži od 1 do 3 odvojenih ili kondenziranih prstena i od 6 do 18 atoma ugljika u prstenu; ili supstituirani ili nesupstituirani cikloalkil, gdje je cikloalkil stabilni 3- do 10-eročlani monociklički ili biciklički radikal, koji je zasićen ili djelomično zasićen; R2 i R3 se neovisno bira između H i supstituirane ili nesupstituirane C1-6 alkilne skupine, po mogućnosti metila; gdje je supstitucija u bilo kojoj od supstituiranih skupina definiranih za R1, R2 i R3 supstitucija na jednom ili više dostupnih položaja s jednom ili više skupina, koje se bira između halogena; cijano; hidroksila; nitro; azido; acila; karboksamido; alkilnih skupina s 1 do 12 atoma ugljika; alkenilnih skupina s jednom ili više nezasićenih veza i s 2 do 12 atoma ugljika; alkinilnih skupina s jednom ili više nezasićenih veza i s 2 do 12 atoma ugljika; alkoksi skupina s jednom ili više kisikovih spojnica i s 1 do 12 atoma ugljika; ariloksi; alkiltio skupina s jednom ili više tioeterskih spojnica i s 1 do 12 atoma ugljika; alkilsulfinilnih skupina s jednom ili više sulfinilnih spojnica i s 1 do 12 atoma ugljika; alkilsulfonilnih skupina s jednom ili više sulfonilnih spojnica i s 1 do 12 atoma ugljika; aminoalkilnih skupina s jednim ili više N atoma i s 1 do 12 atoma ugljika; karbocikličkog arila s 6 ili više ugljika; R4 i R5, zajedno s atomom dušika na kojeg su vezani, tvore supstituirani ili nesupstituirani, nearomatski heterociklil, gdje je heterociklil stabilni 5- ili 6-eročlani prstenasti radikal, koji se sastoji od atoma ugljika i jednog ili više heteroatoma, koje se bira iz skupine koju čine dušik, kisik, te sumpor; gdje je supstitucija u supstituiranom heterociklilu kojeg zajedno tvore R4 i R5 supstitucija na jednom ili više dostupnih položaja s jednom ili više skupina, koje se bira između halogena; cijano; hidroksila; nitro; azido; acila; karboksamido; alkilnih skupina s 1 do 12 atoma ugljika; alkenilnih skupina s jednom ili više nezasićenih veza i s 2 do 12 atoma ugljika; alkinilnih skupina s jednom ili više nezasićenih veza i s 2 do 12 atoma ugljika; alkoksi skupina s jednom ili više kisikovih spojnica i s 1 do 12 atoma ugljika; alkiltio skupina s jednom ili više tioeterskih spojnica i s 1 do 12 atoma ugljika; alkilsulfinilnih skupina s jednom ili više sulfinilnih spojnica i s 1 do 12 atoma ugljika; alkilsulfonilnih skupina s jednom ili više sulfonilnih spojnica i s 1 do 12 atoma ugljika; aminoalkilnih skupina s jednim ili više N atoma i s 1 do 12 atoma ugljika; X predstavlja atom kisika ili skupinu CH-R12, gdje se R12 bira između H, CH3, SH, OH, NH2, CF3, Cl, F, Br, I, te CN; m se bira između 1 i 2; n se bira između 1, 2, 3 i 4; ili njegova farmaceutski prihvatljiva sol, enantiomer, dijastereoizomer ili solvat.
2. Spoj u skladu s patentnim zahtjevom 1, naznačen time što R1 se bira između supstituiranog ili nesupstituiranog ciklopentila, supstituiranog ili nesupstituiranog cikloheksila, supstituiranog ili nesupstituiranog fenial, supstituiranog ili nesupstituiranog naftila, supstituiranog ili nesupstituiranog tiofena, supstituiranog ili nesupstituiranog benzotiofena, supstituiranog ili nesupstituiranog benzofurana, supstituiranog ili nesupstituiranog piridina i supstituiranog ili nesupstituiranog kinolina; gdje je supstitucija bilo kojom od definiranih supstituiranih skupine definirana kao u patentnom zahtjevu 1.
3. Spoj u skladu s patentnim zahtjevom 2, naznačen time što se R1 bira iz skupine koju čine: 2-tienil, 3-tienil, 2,5-diklor-3-tienil, 2,3-diklor-5-tienil, 2,3-diklor-4-tienil, 2-benzotienil, 3-benzotienil, 4-benzotienil, 5-benzotienil, 7-benzotienil, 2-benzofuril, 5-benzofuril, 2-piridil, 3-piridil, 4-piridil, 2-kinolil, 3-kinolil, 5-kinolil, 6-kinolil, 3,4-difluorfenil, 3,4-diklorfenil, ciklopentil, cikloheksil, 7-hidroksi-2-naftil, 6-hidroksi-2-naftil, 5-hidroksi-2-naftil, 6-fluor-2-naftil, 6-metoksi-2-naftil, 6-brom-2-naftil, 6-hidroksimetil-2-naftil, 6-fluormetil-2-naftil, 7-hidroksi-1-naftil, 6-hidroksi-1-naftil, 5-hidroksi-1-naftil, 5-fluor-1-naftil, 5-brom-1-naftil i 1-naftil.
4. Spoj u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačen time što je R2 metil, a R3 je H, ili su R2 i R3 istodobno H ili metil.
5. Spoj u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačen time što R4 i R5 zajedno tvore morfolin-4-ilnu skupinu, piperidinsku skupinu, pirolidinsku skupina ili piperazin-4-ilnu skupinu.
6. Spoj u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačen time što n predstavlja 1 ili 2.
7. Spoj u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačen time što ga se bira iz skupine koju čine: 4-(2-((1-(3,4-diklorfenil)-5-metil-1H-pirazol-3-il)metoksi)etil)morfolin, 4-(2-((5-metil-1-(naftalen-2-il)-1H-pirazol-3-il)metoksi)etil)morfolin, 4-(3-(1-(3,4-diklorfenil)-5-metil-1H-pirazol-3-il)propil)morfolin, 4-(3-(5-metil-1-(naftalen-2-il)-1H-pirazol-3-il)propil)morfolin, 4-(2-(2-(1-(3,4-diklorfenil)-5-metil-1H-pirazol-3-il)etoksi)etil)morfolin, 4-(2-((1-cikloheksil-5-metil-1H-pirazol-3-il)metoksi)etil)morfolin, 4-(3-(1-cikloheksil-5-metil-1H-pirazol-3-il)propil)morfolin, 1-(3,4-diklorfenil)-5-metil-3-((2-(pirolidin-1-il)etoksi)metil)-1H-pirazol, 1-(2-((1-(3,4-diklorfenil)-5-metil-1H-pirazol-3-il)metoksi)etil)piperidin, 1-(4-(2-((1-(3,4-diklorfenil)-5-metil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)etanon, (2S,6R)-4-(2-((1-(3,4-diklorfenil)-5-metil-1H-pirazol-3-il)metoksi)etil)-2,6-dimetilmorfolin, 4-(2-((5-metil-1-(kinolin-3-il)-1H-pirazol-3-il)metoksi)etil)morfolin, 4-(4-(1-(3,4-diklorfenil)-5-metil-1H-pirazol-3-il)butil)morfolin, 4-(3-(5-metil-1-(kinolin-3-il)-1H-pirazol-3-il)propil)morfolin, 4-(2-((1-(3,4-diklorfenil)-1H-pirazol-3-il)metoksi)etil)morfolin, 4-(2-((1-(3,4-diklorfenil)-4,5-dimetil-1H-pirazol-3-il)metoksi)etil)morfolin, 4-(3-(1-(kinolin-3-il)-1H-pirazol-3-il)propil)morfolin, 4-(4-(1-(3,4-diklorfenil)-1H-pirazol-3-il)butil)morfolin, 4-(4-(5-metil-1-(kinolin-3-il)-H-pirazol-3-il)butil)morfolin, 4-(3-((1-cikloheksil-5-metil-1H-pirazol-3-il)metoksi)propil)morfolin, 4-(2-((1-ciklopentil-5-metil-1H-pirazol-3-il)metoksi)etil)morfolin, 1-(4-(2-((1-cikloheksil-5-metil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)etanon-hidroklorid, (3S,5R)-1-(2-((1-cikloheksil-5-metil-1H-pirazol-3-il)metoksi)etil)-3,5-dimetilpiperazin-hidroklorid, 4-(2-(2-(1-cikloheksil-5-metil-1H-pirazol-3-il)etoksi)etil)morfolin-hidroklorid, 4-(2-((1-cikloheksil-1H-pirazol-3-il)metoksi)etil)morfolin-hidroklorid, 4-(2-((1-cikloheksil-4,5-dimetil-1H-pirazol-3-il)metoksi)etil)morfolin-hidroklorid, 1-(4-(2-((1-cikloheksil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)etanon, 1-(4-(3-((1-cikloheksil-1H-pirazol-3-il)metoksi)propil)piperazin-1-il)etanon, 1-(4-(4-((1-cikloheksil-1H-pirazol-3-il)metoksi)butil)piperazin-1-il)etanon, 1-(4-(4-((1-cikloheksil-5-metil-1H-pirazol-3-il)metoksi)butil)piperazin-1-il)etanon, 1-(4-(3-((1-cikloheksil-5-metil-1H-pirazol-3-il)metoksi)propil)piperazin-1-il)etanon, 1-(4-(2-((1-(3,4-diklorfenil)-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)etanon 1-(4-(3-((1-(3,4-diklorfenil)-1H-pirazol-3-il)metoksi)propil)piperazin-1-il)etanon, 1-(4-(4-((1-(3,4-diklorfenil)-1H-pirazol-3-il)metoksi)butil)piperazin-1-il)etanon, 1-(4-(3-((1-(3,4-diklorfenil)-5-metil-1H-pirazol-3-il)metoksi)propil)piperazin-1-il)etanon, 1-(4-(3-((1-(3,4-difluorfenil)-1H-pirazol-3-il)metoksi)propil)piperazin-1-il)etanon, 1-(4-(3-((1-(3,4-difluorfenil)-5-metil-1H-pirazol-3-il)metoksi)propil)piperazin-1-il)etanon, 1-(4-(2-((1-(3,4-difluorfenil)-5-metil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)etanon, 1-(4-(2-((1-(3,4-difluorfenil)-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)etanon, 4-(2-((1-(3,4-difluorfenil)-5-metil-1H-pirazol-3-il)metoksi)etil)morfolin, 4-(2-((1-(3,4-difluorfenil)-1H-pirazol-3-il)metoksi)etil)morfolin, 4-(3-((1-(3,4-difluorfenil)-5-metil-1H-pirazol-3-il)metoksi)propil)morfolin, 1-(4-(2-((1-cikloheksil-5-metil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)propan-1-on, 1-(4-(2-((1-cikloheksil-5-metil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)-2-metilpropan-1-on, 1-(4-(2-((1-cikloheksil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)propan-1-on, 1-(4-(2-((1-cikloheksil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)-2-metilpropan-1-on, 1-(4-(2-((1-(3,4-diklorfenil)-5-metil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)propan-1-on, 1-(4-(2-((1-(3,4-diklorfenil)-5-metil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)-2-metilpropan-1-on, 1-(4-(2-((1-(3,4-diklorfenil)-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)propan-1-on, 1-(4-(2-((1-(3,4-diklorfenil)-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)-2-metilpropan-1-on, ili njihove farmaceutski prihvatljive soli ili solvati.
8. Postupak dobivanja spoja formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 7, ili njegove soli, enantiomera, dijastereoizomera ili solvata, naznačen time što se bira između jednog od sljedećeg: a) postupka koji se sastoji u reakciji spoja formule (II) [image] , u kojoj su R1, R2 i R3 definirani kao u patentnom zahtjevu 1, sa spojem formule (III) [image] , u kojoj su R4, R5 i n definirani kao u patentnom zahtjevu 1, a LG predstavlja izlaznu skupinu; b) postupka koji se sastoji u oksidaciji spoja formule (II) kako bi se dobilo spoj formule (VII) [image] , u kojoj su R1, R2 i R3 definirani kao u patentnom zahtjevu 1, zatim u reakciji spoja formule (VII) s fosfonijevom solju formule (VIII) [image] , u kojoj su R4, R5 i n definirani kao u patentnom zahtjevu 1, kako bi se dobilo spoj formule (IX) [image] , u kojoj su R1, R2, R3, R4, R5 i n definirani kao u patentnom zahtjevu 1, te u redukciji spoja formule (IX); c) postupka koji se sastoji u oksidaciji spoja formule (II) kako bi se dobilo spoj formule (VII) [image] , u kojoj su R1, R2 i R3 definirani kao u patentnom zahtjevu 1, zatim u reakciji spoja formule (VII) s pogodnom fosfonijevom solju, uz naknadnu kiselu hidrolizu kako bi se dobilo spoj formule (XI) [image] , u kojoj su R1, R2, R3 i m definirani kao u patentnom zahtjevu 1, te u redukciji spoja formule (XI), uz naknadnu reakciju sa spojem formule (III) [image] , u kojoj su R4, R5 i n definirani kao u patentnom zahtjevu 1, a LG predstavlja izlaznu skupinu; d) postupka koji se sastoji u reakcija 3-acetil-6-metilpiran-2,4-diona magnezijem, uz naknadnu reakciju sa spojem formule (V): [image] , u kojoj je R1 definiran kao u patentnom zahtjevu 1, kako bi se dobilo spoj formule (XV) [image] , u kojoj je R1 definiran kao u patentnom zahtjevu 1, te u redukciji spoja formule (XV), uz naknadnu reakciju sa spojem formule (III) [image] , u kojoj su R4, R5 i n definirani kao u patentnom zahtjevu 1, a LG predstavlja izlaznu skupinu; e) postupka koji se sastoji u oksidaciji spoja formule (II) kako bi se dobilo spoj formule (VII) [image] , u kojoj su R1, R2 i R3 definirani kao u patentnom zahtjevu 1, zatim u reakciji spoja formule (VII) s fosfonijevom solju formule (XVII) [image] , u kojoj R4, R5, m i n su definirani kao u patentnom zahtjevu 1, kako bi se dobilo spoj formule (XVIII) [image] , u kojoj su R1, R2, R3, R4, R5, m i n definirani kao u patentnom zahtjevu 1, te u redukciji spoja formule (XVIII).
9. Medikament, naznačen time što sadrži najmanje jedan spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 7, ili njegovu farmaceutski prihvatljivu sol, enantiomer, dijastereoizomer ili solvat, kao i farmaceutski prihvatljivu pomoćnu tvar.
10. Spoj formule (I) u skladu s bilo kojim od patentnih zahtjeva 1 do 7, naznačen time što je namijenjen upotrebi kao medikament.
11. Spoj namijenjen upotrebi u skladu s patentnim zahtjevom 10, naznačen time što je medikament namijenjen liječenju i/ili sprječavanju bolesti ili stanja uzrokovanog aktivnošću sigma receptora, gdje bolest ili stanje uključuje proljev; lipoproteinske poremećaje; migrenu; pretilost; povišene razin triglicerida; hilomikronemiju; disbetalipoproteinemiju; hiperlipoproteinemiju; hiperlipidemiju; miješanu hiperlipidemiju; hiperkolesterolemiju; hipertrigliceridemiju; povremenu hipertrigliceridemiju; nasljednu hipertrigliceridemiju; disbetalipoproteinemiju; artritis; hipertenziju; aritmiju; vrijed; poremećaje učenja, pamćenja i pažnje; poremećaje kognitivnih funkcija; neurodegenerativne bolesti; demijelinirajuće bolesti; ovisnost o narkotičniima i kemijskim tvarima, uključujući kokain, amfetamin, etanol i nikotin; tardivnu diskineziju; ishemični inzult; epilepsiju; inzult; stres; rak; psihotična stanja, osobito depreziju, anksioznost ili shizofreniju; upala; te autoimune bolesti.
12. Spoj namijenjen upotrebi u skladu s patentnim zahtjevom 10, naznačen time što je medikament namijenjen liječenju i/ili sprječavanju bolesti ili stanja uzrokovanog aktivnošću sigma receptora, gdje bolest ili stanje uključuje bol, po mogućnosti neuropatsku bol, upalnu bol ili druga bolna stanja, koja uključuju alodiniju i/ili hiperalgeziju.
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SG185720A1 (en) 2012-12-28
TN2012000534A1 (en) 2014-04-01
AR081426A1 (es) 2012-08-29
AU2011257208B2 (en) 2016-05-19
US9181195B2 (en) 2015-11-10
CN103003267B (zh) 2018-05-25
MX2012013667A (es) 2013-02-11

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