HRP20120715T1 - Derivati (tio)karbamoil-cikloheksana kao antagonisti d3/d2 receptora - Google Patents

Derivati (tio)karbamoil-cikloheksana kao antagonisti d3/d2 receptora Download PDF

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HRP20120715T1
HRP20120715T1 HRP20120715TT HRP20120715T HRP20120715T1 HR P20120715 T1 HRP20120715 T1 HR P20120715T1 HR P20120715T T HRP20120715T T HR P20120715TT HR P20120715 T HRP20120715 T HR P20120715T HR P20120715 T1 HRP20120715 T1 HR P20120715T1
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ethyl
cyclohexyl
trans
phenyl
piperazin
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Againe' Csongor Eva
Galambos J�nos
Nogradi Katalin
Vago Istv�n
Gyertyan Istv�n
Kiss Bla
Laszlovszky Istv�n
Laszy Judit
Saghy Katalin
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Richter Gedeon Nyrt
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Abstract

Spoj, naznačen time, da ima formulu (I): gdje R1 i R2 neovisno predstavljaju vodik, ili C1-6 alkil, s ravnim ili razgranatim lancem opcijski supstituiran s jednom ili vi®e od sljedećih skupina: C1-6 alkoksikarbonil, aril, ili (C1-6 alkoksikarbonil)-C1-6 alkil, ili R1 i R2 mogu tvoriti heterociklični prsten sa susjednim atomom du®ika, koji mo·e biti zasićen ili nezasićen opcijski supstituiran monociklički ili biciklički prsten, koji mo·e sadr·avati heteroatome odabrane od O, N ili S, ili C2-7 alkenil s 1 do 3 dvostrukih veza, ili mono-, bi- ili triciklički aril opcijski supstituiran s jednom ili vi®e od sljedećih skupina: C1-6 alkoksi, trifluoro C1-6 alkoksi, C1-6 alkoksikarbonil, C1-6 alkanoil, aril, C1-6 alkiltio, halogen ili cijano, ili opcijski supstituirana mono-, bi- ili triciklička cikloalkil skupina, ili aroil skupina; X predstavlja kisik ili atom sumpora; n je cijeli broj od 1 do 2, i/ili njegovi geometrijski izomeri i/ili stereoizomeri i/ili dijastereomeri i/ili njegove soli i/ili njegovi hidrati i/ili solvati. Patent sadr·i jo® 7 patentnih zahtjeva.

Claims (8)

1. Spoj, naznačen time, da ima formulu (I): [image] gdje R1 i R2 neovisno predstavljaju vodik, ili C1-6 alkil, s ravnim ili razgranatim lancem opcijski supstituiran s jednom ili više od sljedećih skupina: C1-6 alkoksikarbonil, aril, ili (C1-6 alkoksikarbonil)-C1-6 alkil, ili R1 i R2 mogu tvoriti heterociklični prsten sa susjednim atomom dušika, koji može biti zasićen ili nezasićen opcijski supstituiran monociklički ili biciklički prsten, koji može sadržavati heteroatome odabrane od O, N ili S, ili C2-7 alkenil s 1 do 3 dvostrukih veza, ili mono-, bi- ili triciklički aril opcijski supstituiran s jednom ili više od sljedećih skupina: C1-6 alkoksi, trifluoro C1-6 alkoksi, C1-6 alkoksikarbonil, C1-6 alkanoil, aril, C1-6 alkiltio, halogen ili cijano, ili opcijski supstituirana mono-, bi- ili triciklička cikloalkil skupina, ili aroil skupina; X predstavlja kisik ili atom sumpora; n je cijeli broj od 1 do 2, i/ili njegovi geometrijski izomeri i/ili stereoizomeri i/ili dijastereomeri i/ili njegove soli i/ili njegovi hidrati i/ili solvati.
2. Spoj prema zahtjevu 1, naznačen time, da R1 i R2 neovisno predstavljaju vodik, ili C1-6 alkil, s ravnim ili razgranatim lancem opcijski supstituiran s jdnom ili više od sljedećih skupina: C1-6 alkoksikarbonil, fenil ili (C1-6 alkoksikarbonil)-C1-6 alkil, ili R1 i R2 mogu tvoriti heterociklički prsten sa susjednim atomom dušika, koji može biti zasićen opcijski s C1-6 alkilom ili hidroksi supstituiranim monocikličkim prstenom, koji može nadalje sadržavati heteroatome odabrane od O ili N, ili C2-7 alkenil s jednom dvostrukom vezom, ili fenil ili naftil skupina opcijski supstituirana s jednom ili više od sljedećih skupina: C1-6 alkoksi, trifluoro-C1-6 alkoksi, C1-6 alkoksikarbonil, C1-6 alkanoil, aril, C1-6 alkiltio, halogen ili cijano, ili cikloheksil ili adamantil skupina, ili benzoil skupina; X predstavlja kisik ili atom sumpora; n je cijeli broj od 1 do 2, i/ili njegovi geometrijski izomeri i/ili stereoizomeri i/ili dijastereomeri i/ili njegove soli i/ili njegovi hidrati i/ili solvati.
3. Spoj prema zahtjevima 1 ili 2, naznačen time, da R1 i R2 predstavljaju neovisno vodik, ili C1-6 alkil s ravnim ili razgranatim lancem opcijski supstituiran s C1-6 alkoksikarbonilom, ili fenilom, ili R1 i R2 tvore sljedeće prstene, opcijski supstituirane sa C1-6 alkilom ili hidroksi: pirolidin, piperidin ili morfolin prsten. alil; fenil opcijski supstituiran s jednim ili više od sljedećih: C1-6 alkoksi, cijano ili C1-6 alkanoil; cikloheksil; X predstavlja kisik ili sumpor; n je 1, i/ili njegovi geometrijski izomeri i/ili stereoizomeri i/ili dijastereomeri i/ili njegove soli i/ili njegovi hidrati i/ili solvati.
4. Spoj prema bilo kojem zahtjevu od 1 do 3, naznačen time, da je odabran od sljedećih: trans-1-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-3-metil-urea, trans-1-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-3-propil-urea, trans-1-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-3-izopropil-urea, trans-1-{4-[2-[4-(2,3-diklorofenil)-heksahidro[1,4]diazepin-1-il]-etil]-cikloheksil}-3-etil-urea, trans-1-{4-[2-[4-(2,3-diklorofenil)-heksahidro[1,4]diazepin-1-il]-etil]-cikloheksil}-3,3-dimetil-urea, trans-N-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-pirolidin-1-karboksamid, trans-N-{4-[2-[4-(2,3-diklorofenil)-heksahidro[1,4]diazepin-1-il]-etil]-cikloheksil}-pirolidin-1-karboksamid, trans-1-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-3,3-dietil-urea; trans-1-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-3-etil-3-metil-urea; trans-1-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-3-metil-3-propil-urea; trans-1-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-urea; trans-N-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-piperazin-1-karboksamid; trans-N-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-4-metil-piperazin-1-karboksamid; trans-N-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-morfolin-4-karboksamid; trans-N-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-piperidin-1-karboksamid; trans-N-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-4-hydroksi-piperidin-1-karboksamid; trans-1-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-3,3-dimetil-urea; trans-1-{4-[2-[4-(2,3-diklorofenil)-piperazin-1-il]-etil]-cikloheksil}-3-etil-urea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-(2-metoksi-fenil)-urea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-(3-metoksi-fenil)-urea; trans-1-alil-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]- etil}-cikloheksil)-urea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-(2,4-dimetoksi-fenil)-urea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-(2-etoksi-fenil)-urea; trans-1-butil-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-urea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-(4-trifluorometoksi-fenil)-urea; trans-1-adamantan-1-il-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-urea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-(4-metilsulfanil-fenil)-urea; trans-1-bifenil-2-il-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-urea; trans-2-[3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-ureido]-3-metil-butirična kiselina metil ester; trans-2-[3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-ureidol-benzoična kiselina metil ester; trans-1-(3-cijano-fenil)-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-urea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-(3,4,5-trimetoksi-fenil)-urea; trans-1-cikloheksil-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-urea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-fenil-tiourea; trans-1-adamantan-1-il-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-tiourea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-etoksikarbonil-tiourea; trans-1-tert-butil-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-tiourea; trans-1-benzil-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-tiourea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-(2-metoksi-fenil)-tiourea; trans-1-butil-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-tiourea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-propil-tiourea; trans-1-benzoil-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-tiourea; trans-[3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-tioureido]-octena kiselina etil ester; trans-1-(4-(2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-etil-tiourea; trans-1-(4-(2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-naftalen-1-il-tiourea; trans-1-tert-butil-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-urea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-fenil-urea; trans-1-benzil-3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-urea; trans-1-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-3-(4-metoksi-fenil)-urea; trans-[3-(4-{2-[4-(2,3-dikloro-fenil)-piperazin-1-il]-etil}-cikloheksil)-ureido]-octena kiselina etil ester; i/ili njegovi geometrijski izomeri i/ili stereoizomeri i/ili dijastereomeri i/ili njegove soli i/ili njegovi hidrati i/ili solvati.
5. Postupak proizvodnje spoja opće formule (I) prema bilo kojem zahtjevu od 1 do 3, i/ili njegovih geometrijskih izomera i/ili stereoizomera i/ili dijastereomera i/ili soli i/ili hidrata i/ili solvata, naznačen time, da obuhvaća: a) tvorbu amidne veze između (tio)karbamoilklorida formule (II): [image] gdje su R1, R2 i X kao što su gore opisani za formulu (I); i amina formule (III): [image] gdje je značenje za n kao što je gore opisano za formulu (I), ili njegovih derivata, ili b) tvorbu amidne veze između izo(tio)cijanata formule (IV): R1-N=C=X (IV) gdje je značenje od R1 i X kao što je gore opisano za formulu (I), i amina formule (III): [image] gdje je značenje od n kao što je gore opisano za formulu (I), ili njegovih derivata, ili c) pretvorbu in situ amina formule (III) u derivat izo(tio)cijanata i reagiranje potonjeg s aminom formule (V): [image] gdje su R1 i R2kao što su gore opisani za formulu (I), ili njegovih derivata, i međupretvorbu jednog spoja (I) dobivenog bilo kojim od postupaka a) do c), gdje su R1, R2, X i n kao što su definirani za spoj (I), u različiti spoj formule (I) gdje su R1, R2, X i n kao što su definirani za spoj (I); gdje je to pogodno, odvajajući enantiomere i/ili dijastereomere, i/ili cis-i/ili trans-izomere spojeva formule(I), ili njihovih intermedijera gdje su R1, R2, X i n kao što su definirani za spoj (I) pomoću konvencionalnih postupaka; i opcijski nakon toga tvorbu soli i/ili hidrata i/ili solvata.
6. Amin, naznačen time, da ima formulu (III): [image] gdje n je 2, i/ili njegovi zaštićeni oblici i/ili njegovi geometrijski izomeri i/ili stereoizomeri i/ili dijastereomeri i/ili njegove soli i/ili njegovi hidrati i/ili solvati.
7. Farmaceutski sastav, naznačen time, da obuhvaća spoj formule (I) kao što je definiran u bilo kojem zahtjevu od 1 do 4 i/ili njegove geometrijske izomere i/ili stereoizomere i/ili dijastereomere i/ili njegove fiziološki prihvatljive soli i/ili njegove hidrate i/ili solvate i uz to fiziološki prihvatljive nosače.
8. Spoj prema bilo kojem zahtjevu od 1 do 4, naznačen time, da je za uporabu u liječenju i/ili prevenciji stanja odabranog iz skupine koju čine: psihoze kao što je shizofrenija i shizo-afektivni poremećaji, kognitivno oštećenje koje prati shizofreniju, blagi do prosječni kognitivni gubici, demencija, psihotična stanja povezana s demencijom, psihotična depresija, manija, paranoidni i iluzijski poremećaji, diskinetički poremećaji kao što je Parkinson-ova bolest, neuroleptički induciran parkinsonizam i tardivna diskinezija, poremećaji hranjenja kao što je bulimija nervoza, poremećaji pomanjkanja pažnje, poremećaji hiperaktivnosti kod djece, depresija, anksioznost, seksulana disfunkcija, poremećaji spavanja, emezija, agresija, autizam i zlouporaba droga.
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