ME02625B - Jedinjenja pirazola kao inhibitori sigma receptora - Google Patents

Jedinjenja pirazola kao inhibitori sigma receptora

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Publication number
ME02625B
ME02625B MEP-2017-50A MEP5017A ME02625B ME 02625 B ME02625 B ME 02625B ME P5017 A MEP5017 A ME P5017A ME 02625 B ME02625 B ME 02625B
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Montenegro
Prior art keywords
pyrazol
methoxy
methyl
ethyl
compound
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MEP-2017-50A
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German (de)
English (en)
French (fr)
Inventor
López Mónica García
Jover Antoni Torrens
Fernández José Luis Díaz
Moure Ana María Caamaño
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Esteve Labor Dr
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Publication of ME02625B publication Critical patent/ME02625B/me

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Claims (12)

1. Jedinjenje iz opšte formule (I): supstituisani ili nesupstituisani, aromatski ili nearomatski heterociklil, pri čemu je heterociklil stabilan 3-člani do 15-člani prsten radikala koji se sastoji od atoma ugljenika i od jednog do pet heteroatoma izabranih iz grupe koja obuhvata azot, kiseonik, i sumpor; supstituisani ili nesupstituisani aril, pri čemu aril jeste grupa koja obuhvata od 1 do 3 odvojena ili spojena prstena i od 6 do 18 atoma prstena ugljenika; sili supstituisani ili nesupstituisani cikloalkil, pri čemu cikloalkil jeste stabilan 3-člani do 10-člani monociklični ili biciklični radikal koji je zasićen ili delimično zasićen; R2 i R3 se nezavisno biraju iz H i supstituisane ili nesupstituisane C1-6 alkil grupe, preporučljivo metil; pri čemu je supstitucija u bilo kojoj od supstituisanih grupa definisana za R1, R2 i R3 jeste supstitucija na jednom ili više dostupnih pozicija od stane jedne ili više grupa izabranih iz halogen; cijano; hidroksil; nitro; azido; acil; karboksamido; alkil grupe sa 1 do 12 atoma ugljenika; alkenil grupa sa jednim ili više nezasićenih veza i od 2 do 12 atoma ugljenika; alkinil grupa sa jednom ili više nezasićenih veza i od 2 do 12 atoma ugljenika; alkoksi grupe imaju jedan ili više veza kiseonika i od 1 do 12 atoma ugljenika; ariloksi; alkiltio grupe sa jednom ili više veza tioetra i od 1 do 12 atoma ugljenika; alkilsulfinil grupa sa jednom ili više sulfinil veza i od 1 do 12 atoma ugljenika; alkilsulfonil grupe sa jednom ili više sulfonil veza i od 1 do 12 atoma ugljenika; aminoalkil grupe imaju jedan ili više Natoma i od 1 do 12 atoma ugljenika; karbocilični aril ima 6 ili više atoma ugljenika; R4 i R5 zajedno formiraju, sa atomom azota na koji se spoje, supstituisani ili nesupstituisani, nearomatski heterocikl, pri čemu je heterocikl stabilan 5-ili 6-člani prsten radikala koji se sastoji od atoma ugljenika i jednog ili više heteroatoma izabranih iz grupe koja obuhvata azot, kiseonik, i sumpor;pri čemu supstitucija u supstituisanom heterociklu koji R4 i R5 zajedno formiraju jeste supstitucija na jednom ili više dostupnih položaja od strane jedne ili više grupa izabranih iz halogena; cijano; hidroksil; azot, azido; acil; karboksamido; alkil grupa sa 1 do 12 atoma ugljenika; alkenil grupe sa jednom ili više nezasićenih veza i od 2 do 12 atoma ugljenika; alkinil grupa sa jednom ili više nezasićenih veza i od 2 do 12 atoma ugljenika; alkoksi grupe imaju jednu ili više veza kiseonika i od 1 do 12 atoma ugljenika; alkiltio grupe imaju jednu ili više tioetar veza i od 1 do 12 atoma ugljenika; alkilsulfmil grupe sa jednom ili više sulfinil veza i od 1 do 12 atoma ugljenika; alkilsulfonil grupe sa jednom ili više sulfonil veza i od 1 do 12 atoma ugljenika; aminoalkil grupe sa jednim ili više N atoma i od 1 do 12 atoma ugljenika;X predstavlja atom kiseonika ili CH-R12 grupu pri čemu se R12 bira iz H, CH3, SH, OH, NH2, CF3, Cl, F, Br, I, i CN; m se bira iz 1 i 2; n se bira iz 1,2, 3 i 4; ili njihova farmaceutski prihvatljiva so, enantiomer, diastereoizomer ili solvat.
2. Jedinjenje prema patentnom zahtjevu 1, pri čemu se R1 bira iz supstituisanog ili nesupstituisanog ciklopentila, supstituisanog ili nesupstituisanog cikloheksila, supstituisanog ili nesupstituisanog fenila, supstituisanog ili nesupstituisanog naftila, supstituisanog ili nesupstituisanog tiofena, supstituisanog ili nesupstituisanog benzotiofena, supstituisanog ili nesupstituisanog benzofurana, supstituisanog ili nesupstituisanog piridina i supstituisanog ili nesupstituisanog hinolina; pri čemu je supstitucija u bilo kojoj od definisanih supstituisanih grupa kako je definisano u patentnom zahtevu 1.
3. Jedinjenje prema patentnom zahtjevu 2, pri čemu se R1 bira iz grupe koja se sastoji od: 2-tienil, 3-tienil, 2,5- dihloro-3-tienil, 2,3-dihloro-5-tienil, 2,3-dihloro-4-tienil, 2- benzotienil, 3-benzotienil, 4-benzotienil, 5- benzotienil, 7-benzotienil, 2-benzofuril, 5- benzofuril, 2-piridil, 3-piridil, 4-piridil, 2-hinolil, 3-hinolil, 5-hinolil, 6-hinolil, 3,4-difluorofenil, 3,4-dihlorofenil, ciklopentil, cikloheksil, 7-hidroksi-2-naftil, 6-hidroksi-2- naftil, 5-hidroksi-2-naftil, 6-fluoro-2-naftil, 6-metoksi-2-naftil, 6-bromo-2-naftil, 6-hidroksimetil-2-naftil, 6-fluorometil-2-naftil, 7-hidroksi-1-naftil, 6-hidroksi-1-naftil, 5- hidroksi-1- naftil, 5-fluoro-1 -naftil, 5-bromo-1-naftil i 1-naftil.
4. Jedinjenje prema bilo kom od prethodnih patentnih zahtjeva, pri čemu je R2 metil i je H, ili R2 i R3 su istovremeno H ili metil.
5. Jedinjenje prema bilo kom od prethodnih patentnih zahtjeva, pri čemu R4 i R5 formiraju zajedno morfolin-4-il grupu, piperidin grupu, pirolidin grupu ili piperazin-4-il grupu.
6. Jedinjenje prema bilo kom od prethodnih patentnih zahtjeva, pri čemu n predstavlja 1 ili 2.
7. Jedinjenje prema bilo kom od prethodnih patentnih zahtjeva izabranih iz grupe koja obuhvata: 4-(2-((1-(3,4-dihlorofenil)-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-dihlorofenil)-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-dihlorofenil)-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-dihlorofenil)-5-metil-3-((2-(pirolidin-1 -il)etoksi)metil)-1 H-pirazol, 1-(2-((1-(3,4-dihlorofenil)-5-metil-1H-pirazol-3-il)metoksi)etil)piperidin, 1-(4-(2-((1-(3,4-dihlorofenil)-5-metil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)etanon, (2S,6R)-4-(2-((1-(3,4-dihlorofenil)-5-metil-1H-pirazol-3-il)metoksi)etil)-2,6-dimetilmorfolin, 4-(2-((5-metil-1-(hinolin-3-il)-1H-pirazol-3-il)metoksi)etil)morfolin, 4-(4-(1-(3,4-dihlorofenil)-5-metil-1H-pirazol-3-il)butil)morfolin, 4-(3-(5-metil-1-(hinolin-3-il)-1 H-pirazol-3-il)propil)morfolin, 4-(2-((1-(3,4-dihlorofenil)-1H-pirazol-3-il)metoksi)etil)morfolin, 4-(2-((1-(3,4-dihlorofenil)-4,5-dimetil-1H-pirazol-3-il)metoksi)etil)morfolin, 4-(3-(1-(hinolin-3-il)-1H-pirazol-3-il)propil)morfolin, 4-(4-(1 -(3,4-dihlorofenil)-1 H-pirazol-3-il)butil)morfolin, 4-(4-(5-metil-1-(hinolin-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 hidrohlorid, (3S,5R)-1-(2-((1-cikloheksil-5-metil-1H-pirazol-3-il)metoksi)etil)-3,5-dimetilpiperazin hidrohlorid, 4-(2-(2-(1-cikloheksil-5-metil-1H-pirazol-3-il)etoksi)etil)morfolin hidrohlorid, 4-(2-((1-cikloheksil-1H-pirazol-3-il)metoksi)etil)morfolin hidrohlorid, 4-(2-((1-cikloheksil-4,5-dimetil-1H-pirazol-3-il)metoksi)etil)morfolin hidrohlorid, 1-(4-(2-((1-cikloheksil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)etanon, 1 -(4-(3-(( 1 -cikloheksil-1 H-pirazol-3-il)metoksi)propil)piperazin-1-il)etanon, 1-(4-(4-((1-cikloheksil-1 H-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-dihlorofenil)-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)etanon 1-(4-(3-((1-(3,4-dihlorofenil)-1H-pirazol-3-il)metoksi)propil)piperazin-1-il)etanon, 1-(4-(4-((1-(3,4-dihlorofenil)-1H-pirazol-3-il)metoksi)butil)piperazin-1-il)etanon, 1-(4-(3-((1-(3,4-dihlorofenil)-5-metil-1H-pirazol-3-il)metoksi)propil)piperazin-1-il)etanon, 1-(4-(3-((1-(3,4-difluorofenil)-1H-pirazoI-3-il)metoksi)propil)piperazin-1-il)etanon, 1-(4-(3-((1-(3,4-difluorofenil)-5-metil-1H-pirazol-3-il)metoksi)propil)piperazin-1-il)etanon, 1-(4-(2-((1-(3,4-difluorofenil)-5-metil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)etanon, 1-(4-(2-((1-(3,4-difluorofenil)-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)etanon, 4-(2-((1-(3,4-difluorofenil)-5-metil-1H-pirazol-3-il)metoksi)etil)morfolin, 4-(2-((1-(3,4-difluorofenil)-1H-pirazol-3-i!)metoksi)etil)morfolin, 4-(3-((1-(3,4-difluorofenil)-5-metil-1H-pirazol-3-il)metoksi)propil)morfolin, 1-(4-(2-((1-cikloheksil-5-metil-1H-pirazol-3-il)methoksi)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-1 H-pirazol-3-il)metoksi)etil)piperazin-1-il)propan-1-on, 1 -(4-(2-(( 1 -cikloheksil-1 H-pirazol-3-il)metoksi)etil)piperazin-1 -il)-2-metilpropan-1-on, 1-(4-(2-((1-(3,4-dihlorofenil)-5-metil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)propan-1-on, 1-(4-(2-((1-(3,4-dihlorofenil)-5-metil-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)-2-metilpropan 1- on, 1-(4-(2-((1-(3,4-dihlorofenil)-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)propan-1-on, 1-(4-(2-((1-(3,4-dihlorofenil)-1H-pirazol-3-il)metoksi)etil)piperazin-1-il)-2-metilpropan-1-on, ili njegova farmaceutski prihvatljiva so ili solvat.
8. Postupak za pripremu jedinjenja iz formule (I) kako je defiinisano u bilo kom od patentnih zahtjeva 1 do 7, ili njegove soli, enantiomera, diastereoizomera ili solvata, koji se bira iz jednog od sledećih: a) postupak koji obuhvata reakciju jedinjenja iz formule (II) u kom R1, R2 i R3 jesu kako je definisano u patentnom zahtevu 1, sa je dinjenjem iz formule (III) u kom su R4, R5 i n jesu kao što je definisano u patentnom zahtevu 1 i LG predstavalja izlaznu grupu; b) proces koji obuhvata oksidaciju jedinjenja iz formule (II) da se dobije jedinjenje iz formule (VII) u kojoj su R1, R2 i R3 kao što su definisani u patentnom zahtjevu 1, posle čega sledi reakcija jedinjenja iz formule (VII) sa solju fosfonijuma iz formule (VIII) u kojoj su R4, R5 i n kao što su definisani u patentnom zahtjevu 1, da se dobije jedinjenje iz formule (IX) u kojoj su R1, R2, R3, F4, R5, i n kao što je definisano u patentnom zahtevu 1, i smanjenje jedinjenja iz formule (IX); c) proces koji obuhvata oksidaciju jedinjenja iz formule (II) da se dobije jedinjenje iz formule (VII) u kojoj su R1, R2 i R3 kao što su definisani u patentnom zahtevu 1, posle čega je usledila reakcija jedinjenja iz formule (VII) sa pogodnom solju fosfonijuma i naknadnom hidrolizom kiseline da se dobije jedinjenje iz formule (XI) u kojoj su R1, R2, R3 i m kao što su definisani u patentnom zahtjevu 1, redukcija jedinjenja iz formule (XI) i naknadna reakcija sa jedinjenjem iz formule (III) u kojoj su R4, R5 i n kao što je definisano u patentnom zahtjevu 1 i LG predstavlja izlaznu grupu; d) postupak koji obuhvata reakciju 3-acetil-6-metil-piran-2,4-diona sa magnezijumom i naknadnu reakciju sa jedinjenjem iz formule (V): u kojoj je R1 kao što je definisano u patentnom zahtjevu 1, da se dobije jedinjenje iz formule (XV) u kojoj je R1 kao što je definisano u patentnom zahtjevu 1, i redukcija jedinjenja iz formule (XV) i naknadna reakcija sa jedinjenjenjem iz formule (III) u kom su R4, R5 i n kao što je definisano u patentnom zahtjevu 1 i LG predstavlja izlaznu grupu; e) proces koji obuhvata oksidaciju jedinjenja iz formule (II) da se dobije jedinjenje iz formule (VII) u kojoj su R1, R2, R3 kao što je definisano u patentnom zahtjevu 1, posle čega sledi reakcija jedinjenja iz formule (VII) sa solju fosfonijuma iz formule (XVII) u kojoj su R4, R5, m i n kao što su definisani u patentnom zahtjevu 1, da se dobije jedinjenje iz formule (XVIII) u kojoj su R1, R2, R3, R4, R5, m i n kao što su definisani u patentnom zahtjevu 1, i redukciji jedinjenja iz formule (XVIII).
9. Lijek koji obuhvata barem jedno jedinjenje iz formule (I) kao što je definisano u bilo kom od patentnih zahtjeva 1 do 7, ili njegova farmaceutski prihvatljiva so, enantiomer, diastereoizomer ili solvat i farmaceutski prihvatljiv ekscipijent.
10. Jedinjenje iz formule (I) kako se definiše u bilo kom od patentnih zahtjeva 1 do 7 za upotrebu kao lek.
11. Jedinjenje za upotrebu prema patentnom zahtjevu 10, pri čemu je lijek za liječenje i/ili suzbijanje pojave bolesti ili stanja posredovane sigma receptorom, pri čemu bolest ili stanje obuhvata proliv; poremećaje lipoproteina; migrene; gojaznost; povišene nivoe triglicerida; hilomikronemiju; disbetalipoproteinemiju; hiperlipoproteinemiju; hiperlipidemiju; mešanu hiperlipidemiju; hiperholesterolemiju; hipertrigliceridemiju; sporadičnu hipertrigliceridemiju; nasleđenu hipertrigliceridemiju; disbetalipoproteinemiju; artritis; hipertenziju; aritmiju; čir; poteškoće sa učenjem, pamćenjem i probleme u obliku nedostatka pažnje; kognitivne poremećaje; neurodegenerativne bolesti; demijelinišuće bolesti; zavisnost od droga i hemijskih supstanci uključujući kokain, amfetamin, etanol i nikotin; tardivna diskinezija; ishemijski moždani udar; epilepsija; moždani udar; stres; kancer: psihotična stanja, posebno depresija, uznemirenost ili šizofrenija; upala; ili autoimune bolesti.
12. Jedinjenje za upotrebu prema patentnom zahtjevu 10, pri čemu je lijek za liječenje i/ili sprečavanje pojave bolesti ili stanja posredovane sigma receptorom, pri čemu bolest ili stanje obuhvata bol, preporučljivo neuropatski bol, zapaljenski bol ili druga stanja bolesti koja obuhvataju alodiniju i/ili hiperalgeziju.
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UA112160C2 (uk) 2016-08-10
TWI507195B (zh) 2015-11-11
HUE031755T2 (hu) 2017-07-28
MX338226B (es) 2016-04-08
US20130158029A1 (en) 2013-06-20
KR101819680B1 (ko) 2018-01-17
JP5932779B2 (ja) 2016-06-08
RS55750B1 (sr) 2017-07-31

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