HRP20050784A2 - New modulators of dopamine neurotransmission - Google Patents
New modulators of dopamine neurotransmission Download PDFInfo
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- HRP20050784A2 HRP20050784A2 HR20050784A HRP20050784A HRP20050784A2 HR P20050784 A2 HRP20050784 A2 HR P20050784A2 HR 20050784 A HR20050784 A HR 20050784A HR P20050784 A HRP20050784 A HR P20050784A HR P20050784 A2 HRP20050784 A2 HR P20050784A2
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Classifications
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Abstract
Otkriveni su novi 3-supstituirani 4-(fenil-N-alkil)-piperazinski i 4-(fenil-N-alkil)-piperidinski spojevi Formule (1), gdje je X N, CH ili C, međutimX može biti samo C kada spoj obuhvaća dvostruku vezu na točkastoj crti; R1 je OSO2CF3, OSO2CH3, SOR3, SO2R3, COR3, NO2 ili CONHR3 i kada je X CH ili C, R1 također može biti CF3, CN, F, Cl, Br ili I; R2 je C1-C4 alkil, neki alil, CH2SCH3, CH2CH2OCH3,CH2CH2CH2F, CH2CF3, 3,3,3-trifluorpropil, 4,4,4-trifluorbutil ili -(CH2)-R4; R3 je C1-C3 alkil, CF3ili N(R2)2; R4 je C3-C6 cikloalkil, 2-tetrahidrofuran ili 3-tetrahidrofuran, kao i njihove farmaceutski prihvatljive soli. Također su otkriveni farmaceutski pripravci gornjih spojeva i načini kada segornji spojevi koriste za tretiranje poremećaja usredišnjem živčanom sustavu.
Description
Polje izuma
Sadašnji izum se odnosi na nove modulatore neurotransmisije dopamina, specifičnije na nove supstituirane 4-(fenil-N-alkil)-piperazine i 4-(fenil-N-alkil)-piperidine i njihovu uporabu.
Pozadina izuma
Dopamin je neurotransmiter u mozgu. Otkada je otkriven u 1950-tim, funkcija dopamina u mozgu je intenzivno istraživana. Do danas je dobro utvrđeno da je dopamin bitan u nekoliko aspekata funkcije mozga, uključujući motorne, spoznajne, osjetilne, emocionalne i autonomne (na primjer regulacija teka, tjelesne temperature, spavanje) funkcije. Stoga modulacija dopaminergičkih funkcija može biti korisna u tretiranju širokog raspona poremećaja koji napadaju funkcije mozga. U stvari, i neurološki i psihijatrijski poremećaji se tretiraju lijekovima temeljenim na interakcijama s dopaminskim sustavom i dopaminskim receptorima u mozgu.
Lijekovi koji djeluju, izravno ili neizravno, na dopaminske receptore se uobičajeno koriste u tretiranju neuroloških i psihijatrijskih poremećaja, na primjer Parkinsonove bolesti i šizofrenije. Trenutno dostupni dopaminergički farmaceutici imaju jaka pokrajna djelovanja, kao što su ekstrapiramidalni pokrajni učinci i tardivna diskinezija kod dopaminergičkih antagonista korištenih kao antipsihotička sredstva, i diskinezije i psihoze kod dopaminergičkih agonista korištenih kao sredstva protiv Parkinsonove bolesti. Terapijski učinci su nezadovoljavajući u mnogim pogledima. Za poboljšanje djelotvornosti i smanjenja pokrajnih učinaka dopaminergičkih farmaceutika se traže novi dopamin receptorski ligandi sa selektivnosti na specifičnim dopaminskim receptorskim podvrstama ili regionalnom selektivnosti. U ovom kontekstu, također djelomični dopaminski receptorski agonisti, to jest dopaminski receptorski ligandi s nekom, ali ne potpunim, intrinsičnim djelovanjem na dopaminske receptore, su razvijeni radi dostizanja optimalnog stupnja stimulacije dopaminskih receptora, izbjegavajući suvišnu dopaminsku receptorsku blokadu ili suvišnu stimulaciju.
O spojevima koji pripadaju razredu supstituiranih 4-(fenil-N-alkil)-piperazina i supstituiranih 4-(fenil-N-alkil)-piperidina je već ranije izvješteno. Među tim spojevima, neki su nedjelotvorni u CNS (središnjem živčanom sustavu), neki pokazuju serotonergičke ili miješovito serotonergetičko/dopaminergičke farmakološke profile, dok su neki potpuni ili djelomični dopamin receptorski agonisti ili antagonisti s visokom djelotvornošću za dopaminske receptore.
Brojni derivati 4-fenilpiperazina i 4-fenilpiperidina su poznati i opisani, na primjer Costall i ostali, European J. Pharm. 31, 94, (1975), Mewshaw i ostali, Bioorg. Med. Chem. Lett., 8, 295, (1998). Navedeni spojevi su supstituirani 4-fenilpiperazini, većina njih je 2-, 3- ili 4-OH fenil supstituirana i pokazuju svojstva DA autoreceptor agonista.
Fuller R.W. i ostali, J. Pharmacol. Exp. Therapeut. 218, 636, (1981) otkrivaju supstituirane piperazine (na primjer 1-(m-trifluor-metilfenil)piperazin) koji prema izvješću djeluje kao serotoninski agonist i inhibira uzimanje serotonina. Fuller R.W. i ostali, Res. Commun. Chem. Pathol. Pharmacol. 17, 551, (1977) otkrivaju komparativna djelovanja na 3,4-dihidroksi-feniloctenu kiselinu i Res. Commun. Chem. Pathol. Pharmacol. 29, 201, (1980) otkriva komparativne učinke na koncentraciju 5-hidroksiindol octene kiseline u mozgu štakora s 1-(p-klorfenol)-piperazinom.
Boissier J. i ostali, Chem. Abstr. 61:10691c, otkrivaju disupstituirane piperazine. Spojevi su prema izvješću adrenolitici, antihipertenzivi, pojačivači djelovanja barbiturata i depresanti središnjeg živčanog sustava.
Brojni različito supstituirani piperazini su objavljeni kao ligandi na 5-HT1A receptore, na primjer Glennon R.A. i ostali, J. Med. Chem., 31, 1968, (1988), van Steen B.J., J. Med. Chem., 36, 2751, (1993), Mokrosz, J. i ostali, Arch. Pharm. (Weinheim) 328, 143-148 (1995) i Dukat M.-L., J. Med. Chem., 39, 4017, (1996). Glennon R.A. otkriva, u međunarodnoj patentnoj prijavi WO 93/00313 i WO 91/09594 različite amine, među njima supstituirane piperazine, kao sigma receptorske ligande. Klinička proučavanja svojstava sigma receptorskih liganada kod pacijenata sa šizofrenijom nisu dala dokaz antipsihotičkog djelovanja, ili djelovanja na bilo koji drugi CNS poremećaj. Dva od najviše proučavanih selektivnih sigma receptorskih antagonista, BW234U (rimkazol) i BMY14802, su oba propala na kliničkim proučavanjima pacijenata sa šizofrenijom (Borison i ostali, 1991., Psychopharmacol. Bull., 27(2): 103-106; Gewirtz i ostali, 1994., Neuropsychopharmacology, 10:37-40).
Dalje, WO 93/04684 i GB 2027703 također opisuju specifično supstituirane piperazine korisne u tretiranju CNS poremećaja.
Sažetak izuma
Cilj sadašnjeg izuma je osigurati nove farmaceutski aktivne spojeve, osobito korisne u tretitanju poremećaja središnjeg živčanog sustava, koji nemaju nedostatke gore opisanih tvari.
U radu koji je vodio sadašnjem izumu je nađeno da je poželjno osigurati tvari sa specifičnim farmakološkim svojstvima, to jest tvari koje imaju modulatorska djelovanja na neurotransmisiju dopamina. Ovakva svojstva nisu opisana ranije i nije ih moguće dobiti s ranije poznatim spojevima. Spojevi prema sadašnjem izumu imaju vrlo iznenađujući i zanimljiv dvostruki profil dopaminergičkog djelovanja s učincima poput antagonista na neurokemiju mozga i umjerenim djelovanjima poput agonista na normalno ponašanje, ali oni induciraju inhibiciju ponašanja u stanjima hiperaktivnosti.
Sadašnji izum se stoga odnosi na nove 3-supstituirane 4-(fenil-N-alkil) piperazine i 3-supstituirane 4-(fenil-N-alkil) piperidine u obliku slobodne baze ili njihovih farmaceutski prihvatljivih soli, farmaceutskih pripravaka koji sadrže rečene spojeve i uporabu rečenih spojeva u terapiji.
Jedan predmet izuma je osigurati nove spojeve za terapijsku uporabu, i određenije spojeve za modulaciju dopaminenergičkih sustava u mozgu sisavaca, uključujući ljudski mozak.
Drugi predmet izuma je osigurati spojeve s terapijskim učincima nakon oralnog davanja.
Određenije, sadašnji izum se odnosi na 3-supstituirane 4-(fenil-N-alkil)-piperazinske i 4-(fenil-N-alkil)-piperidinske spojeve Formule (1):
[image]
i njihove farmaceutski prihvatljive soli,
gdje
je X odabran iz skupine koja se sastoji iz N, CH i C, međutim X može biti samo C kada spoj obuhvaća dvostruku vezu na točkastoj crti;
je R1 odabran iz skupine koja se sastoji iz OSO2CF3, OSO2CH3, SOR3, SO2R3, COR3, NO2 i CONHR3, gdje je R3 kako je određen gore, i kada je X CH ili C, R1 također može biti odabran iz skupine koja se sastoji iz CF3, CN, F, Cl, Br i I;
je R2 odabran iz skupine koja se sastoji iz C1-C4 alkila, nekih alila, CH2SCH3, CH2CH2OCH3, CH2CH2CH2F, CH2CF3, 3,3,3-trifluorpropil, 4,4,4-trifluorbutil i -(CH2)-R4, gdje je R4 kako je određen gore;
je R3 odabran iz skupine koja se sastoji iz C1-C3 alkila, CF3 i N(R2)2; gdje je R2 kako je određen gore;
je R4 odabran iz skupine koja se sastoji iz C3-C6 cikloalkila, 2-tetrahidrofurana i 3-tetra-hidrofurana.
Spojevi prema sadašnjem izumu posjeduju dopamin modulacijska svojstva i korisni su kod tretiranja brojnih poremećaja središnjeg živčanog sustava, uključujući i psihijatrijske i neurološke simptome.
Oboljenja u kojima spojevi s modulacijskim učincima na dopaminergičkim sustavima mogu biti korisni su oboljenja povezana sa starenjem, za spriječavanje bradikinezije i depresije i za poboljšanje mentalnih funkcija. Oni se također mogu koristiti za poboljšanje kognitivnih funkcija i povezanih emocionalnih poremećaja kod neurodegenerativnih i razvojnih poremećaja kao i nakon oštećenja mozga.
Spojevi prema izumu se mogu koristiti za poboljšanje svih simptoma psihoza, uključujući šizofreniju i šizofrenične poremećaje kao i kod lijekovima induciranih psihotičkih poremećaja. Spojevi prema izumu se također mogu koristiti i kod poremećaja ponašanja obično prvo dijagnosticiranih u ranom djetinjstvu, djetinjstvu i mladenačkoj dobi kao i kod impulzivnih poremećaja. Također se mogu poboljšati poremećaji govora kao što je mucanje. Također se mogu koristiti za tretiranje poremećaja uzrokovanih zloupotrebom tvari kao i poremećaja koje karakterizira zloupotreba hrane.
Poremećaji raspoloženja i tjeskobe, poremećaji ličnosti i konverzijska histerija se također mogu tretirati sa spojevima prema izumu.
Neurološke indikacije uključuju tretiranje Huntingtonovog oboljenja i ostalih poremećaja kretanja kao i poremećaja kretanja induciranih s lijekovima. Nemirne noge i povezana oboljenja kao i narkolepsija se također mogu tretirati sa spojevima uključenim prema izumu. Oni također mogu poboljšati mentalne i motoričke funkcije kod Parkinsonovog oboljenja, i kod povezanih parkinsonskih sindroma. Oni se također mogu koristiti za poboljšanje drhtanja različitog podrijetla. Oni se mogu koristiti u tretiranju glavobolja i za poboljšanje funkcija mozga nakon vaskularnih ili traumatskih ozljeda mozga. Štoviše, mogu se koristiti za oslobađanje boli u stanjima karakteriziranim povećanim mišičnim tonusom.
Za spojeve prema sadašnjem izumu je neočekivano pronađeno da djeluju specifično na dopaminergički sustav u mozgu. Imaju djelovanje na biokemijske indices u mozgu s karakterističnim oblicima selektivnih dopaminskih antagonista, na primjer proizvodeći povećanje koncentracije dopaminskih metabolita.
Ipak, dopaminski receptorski antagonisti karakteristično potiskuju aktivnost ponašanja i induciraju katalepsiju, dok spojevi iz ovog izuma ne pokazuju, ili samo ograničeno, inhibitorsko djelovanje na spontano pokretanje. Nasuprot oni mogu inducirati laganu aktivaciju ponašanja s usporednim povećanjem malih pokreta, na primjer zaustavljanje u središtu arene za snimanje ponašanja, slično onome induciranom od dopaminergičkih agonista. Aktivacija ponašanja je ograničena, ne dostiže pronađeno povećanje aktivnosti inducirano s izravnim ili neizravnim dopaminergičkim agonistima. S druge strane, poželjne tvari smanjuju povećanje aktivnosti inducirane izravnim ili neizravnim dopaminergičkim agonistima, to jest d-amfetamin i slični.
Stoga, spojevi iz ovog izuma iznenađujuće pokazuju zanimljivi dvostruki dopaminergički profil djelovanja s učincima poput antagonista na neurokemiju mozga i blage učinke poput agonista na normalno ponašanje, ali inhibiciju ponašanja u stanju hiperaktivnosti. Profil djelovanja navodi na modulatorne učinke na dopaminergičke funkcije, jasno različite od poznatih spojeva koji pripadaju ovim kemijskim razredima ili učinke predvidljive od tipičnihdopaminskih receptorskih antagonista ili agonista od ovih ili drugih kemijskih razreda.
Obzirom na uključenost dopamina u različitim CNS funkcijama i kliničke nedostatke za sada dostupnih farmaceutika koji djeluju na dopaminske sustave, novi razred dopaminergičkih modulatora prisutnih u ovom izumu mogu dokazati nadmoć prema do sada poznatim dopaminergičkim spojevima kod tretiranja nekoliko poremećaja povezanih sa poremećajima CNSa, obzirom na učinkovitost kao i pokrajne učinke.
Za neke spojeve prema izumu je nađeno da imaju iznenađujuće dobre farmakokinetičke osobine uključujući visoku oralnu biodostupnost. Oni su stoga pogodni za pripravu farmaceutika koji se daju oralno. Ne postoji vodič u ranijim saznanjima (stanju tehnike) kako dobiti spojeve s ovim učinkom na dopaminske sustave u mozgu.
Detaljan opis izuma
Farmakologija
Dostupan je dokaz da je neurotransmisija u CNSu poremećena kod psihijatrijskih i neuroloških poremećaja. U mnogim slučajevima, na primjer kod šizofrenije ili Parkinsonove bolesti, je farmakoterapija temeljena na antagonizmu ili agonizmu na dopaminskim receptorima korisna, ali nije optimalna. Prethodnih godina je mnogo truda uloženo na pronalaženje novih i selektivnih liganada za dopaminske receptorske podvrste (D1,D2, D3, D4, D5) s ciljem poboljšanja učinkovitosti i smanjenja pokrajnih učinaka.
Sadašnji izum nudi drugo načelo za nove terapeutike temeljene na međudjelovanju s dopaminskim sustavima. Spojevi prema izumu imaju učinke na neurokemiju mozga slično antagonistima kod dopaminskih D2 receptora. Suprotno trenutno korištenim dopaminskim receptorskim antagonistima, spojevi prema izumu ne pokazuju ili pokazuju ograničeno inhibitorske učinke na spontano kretanje. Oni mogu inducirati aktivaciju ponašanja s istovremenim povećanjem malih pokreta, na primjer zaustavljanje u središtu arene za snimanje ponašanja, slično onome induciranom od dopaminergičkih agonista. Aktivacija ponašanja je ograničena, ne dostiže pronađeno povećanje aktivnosti inducirano izravno ili neizravno s dopaminskim receptorskim agonistima. Iznenađujuće, poželjne tvari mogu stvarno smanjiti povećanje aktivnosti inducirano izravno ili neizravno dopaminergičkim agonistima, to jest d-amfetaminom i sličnima.
Poželjne strukture su supstituirane u meta položaju aromatskog prstena. Jedan primjer takvog spoja je metansulfonska kiselina 3-(1-propil-piperidin-4-il)-fenilni ester, koji je pokazan u Primjeru 14 niže. Kod štakora ovaj spoj povećava 3,4-dihidroksifeniloctenu kiselinu u striatumu od 1265 ± 74 (nadzori) na 3208 ± 236 ng/g tkiva kod 50 µmola/kg s.c. u kombinaciji s laganim porastom aktivnosti ponašanja; 1485 ± 328 cm/30 min (nadzori) na 2126 ± 240 cm/30 min kod 50 µmola/kg s.c., n=4. Drugi poželjni primjer spoja spoja prema izumu je 4- (3-metansulfonil-fenil)-1-propil-piperidin, dalje prikazan u Primjeru 6. Kod štakora ovaj spoj povećava 3,4-dihidroksi-feniloctenu kiselinu u striatumu od 914 ± 19 (nadzori) na 1703 ± 19 ng/g tkiva kod 50 µmola/kg s.c. Ovo povećanje u prometu dopamina slijedi trend prema povećanju motoričke aktivnosti od 2030 ± 299 cm/60 min na 2879 ± 398 cm/60 min p = 0,14. Kod životinja priviknutih na mjerač pokretljivosti, spoj opisan u Primjeru 6, 4- (3-metansulfonil-fenil)-1-propil-piperidin, povećava aktivnost ponašanja od 476 ± 279 cm/60 min (nadzori) na 1243 ± 72 cm/60 min, p < 0,05, n = 4 i 4-dihidroksifeniloctenu kiselinu u striatumu od 975 ± 23 (nadzori) na 2074 ± 144 ng/g tkiva kod 50 µmola/kg s.c., p < 0,05, n = 4.
Dodatno, spoj opisan u Primjeru 6, 4- (3-metansulfonil-fenil)-1-propil-piperidin, ima poželjnu sposobnost smanjenja aktivacije ponašanja inducirane i s d-amfetaminom (1,5 mg/kg s.c.) i dizolcipinom (Mk-801, 0,7 mg/kg i.p.). Hiperaktivnost uzrokovana s d-amfetaminom je smanjena od 10694 ± 2165 cm/60 min na 1839 ± 344 cm/60 min, p < 0,05, n = 4, kod 50 s.c. spoja opisanog u Primjeru 6 i aktivacija ponašanja inducirana s dizolcipinom (Mk-801) je smanjena od 32580 ± 4303 cm/60 min p < 0,05, kod 50 µmola/kg s.c. Iznenađujuće, spoj opisan u Primjeru 6 ima oralnu dostupnost (F) 85% kod štakora.
Za razliku od donekle sličnih spojeva opisanih u WO91/09594, spoj iz Primjera 6, 4- (3-metansulfonil-fenil)-1-propil-piperidin, nema afinitet prema sigma receptoru, < 50% inhibicije [3H] -DTG vezanja (prema načinu za mjerenje sigma vezanja opisanog od Shirayama i ostali, 1993., Eur. J. Pharmacol. 237, str. 117) kod 10 µmol/L na membrane mozga štakora.
S ciljem pokazivanja iznenađujućih učinaka spojeva prema izumu, neki od spojeva su uspoređeni sa sličnim spojevima prema ranijim saznanjima (stanju tehnike). Spojevi korišteni za uspoređivanje sa spojevima prema izumu u usporednim primjerima stoga nisu spojevi prema izumu dok ne pokazuju željena svojstva.
Usporedni primjer 1: 4- (4-metansulfonil-fenil)-1-propil-piperidin pokazuje da supstitucija u para položaju daje neaktivne spojeve. 4- (4-Metansulfonil-fenil)-1-propil-piperidin nema učinka na 3,4-dihidroksifenil-octenu kiselinu u striatumu kako je pokazano u neurokemijskom pokusu; 988 ± 70 (nadzori) ng/g tkiva i 928 ± 51 ng/g tkiva kod 50 µmola/kg s.c. 4- (4-Metansulfonil-fenil)-1-propil-piperidin nema željena svojstva prema izumu.
Usporedni primjer 2: Radi daljnjeg pokazivanja važnosti supstitucije na aromatskom prstenu za željena svojstva, za 4-fenil-1-propil-piperidin je pokazan nedostatak aktivnosti kod testa ponašanja kod ne predtretiranog štakora, 3661 ± 494 cm/60 min, nadzori, na 2553 ± 471 cm/60 min, p < 0,05, n = 4, kod 33 µmola/kg i nedostatak učinaka na 3,4-dihidroksifenil-octenu kiselinu u striatumu kako je pokazano u neurokemijskom pokusu; 1027 ± 31 (nadzori) ng/g tkiva i 1190 ± 70 ng/g tkiva kod 33 µmola/kg s.c., p > 0,05, 4-fenil-1-propil-piperidin također nema željenu inhibiciju aktivnosti ponašanja kod stimuliranog s d-amfetaminom (17295 ± 4738 cm/60 min, d-amfetamin, na 13764 ± 2919 cm/60 min, n = 4, p >> 0,05 kod 33 µmola/kg.
Usporedni primjer 3: Nadalje, za 1-fenil-4-propil-piperazin, opisan kao spoj koji se veže na sigma receptor u WO91/09594, je nađeno da smanjuje aktivnost ponašanja kod ne predtretirane životinje, od 3370 ± 227, nadzori, na 1923 ± 204 cm/60 min, n = 4, p < 0,05 kod 33 µmola/kg s.c., što znači da nema tražena svojstva.
Usporedni primjer 4: Supstitucija u orto položaju kao što je primjerice 1-(2-metoksi-fenil)-4-propil piperazin daje spoj koji povećava 3,4-dihidroksifeniloctenu kiselinu u striatumu od 1028 ± 9 (nadzori) ng/g tkiva na 3836 ± 65 ng/g tkiva kod 50 µmola/kg s.c., p < 0,05, n = 4. Nakon toga slijedi inhibicija ponašanja koja se ne traži za sadašnji izum; 11651 ± 300 cm/60 min (nadzori) na 67 ± 34 cm/60 min, kod 50 µmola/kg s.c., p < 0,05,
n = 4.
Usporedni primjer 5: Svojstva supstituenta u meta položaju su važna. 1-Propil-4-(3-trifluor-metil-fenil) piperazin povećava 3,4-dihidroksifenil-octenu kiselinu u striatumu od 1066 ± 46 (nadzori) ng/g tkiva na 3358 ± 162 ng/g tkiva kod 50 µmola/kg s.c., p < 0,05,
n = 4, međutim, nakon toga slijedi inhibicija ponašanja od 1244 ± 341 cm/60 min (nadzori) na 271 ± 137 kod 50 µmola/kg s.c., p < 0,05, n = 4, stoga, nedostaju svojstva koja se traže u sadašnjem izumu.
Usporedni primjer 6: Nadalje, spoj 3-(4-propil-piperazin-1-il)-benzonitril povećava 3,4-dihidroksifenil-octenu kiselinu u striatumu od 1432 ± 57 (nadzori) ng/g tkiva na 4498 ± 243 ng/g tkiva kod 100 µmola/kg s.c., p < 0,05, n = 4, i smanjuje 5-hidroksiindol octenu kiselinu od 630 ± 16 (nadzori) ng/g tkiva na 484 ± 26 ng/g tkiva kod 100 µmola/kg s.c.,
p < 0,05, n = 4. Nakon ovih učinaka slijedi inhibicija ponašanja od 3959 ± 688 cm/60 min (nadzori) na 634 ± 266 kod 100 µmola/kg s.c., p < 0,05, n = 4, stoga nema svojstva koja se traže u sadašnjem izumu. 3-(4-Propil-piperazin-1-il)-benzonitril ima slijedeća svojstva: t.t. 159 ̊C (fumarat) MS m/z (relativni intenzitet, 70 eV) 229 (M+, 28), 200 (bp), 157 (27), 129 (22), 70 (25).
Usporedni primjer 7: Jedan drugi primjer važnosti supstituenta je priprava 14 koja nema utjecaja na 3,4-dihidroksi-fenil-octenu kiselinu u striatumu; 1121 ± 36 (nadzori) ng/g tkiva na 1169 ± 42 ng/g tkiva kod 50 µmola/kg s.c.
Usporedni primjer 8: Fizikalno-kemijska svojstva supstituenta na bazičnom dušiku su također važna za željeni profil. Nije moguće koristiti bilo koji supstituent, koji je kao primjer 1-feniletil-4-(3-trifluormetil-fenil)-piperazin opisan kao ligand sigma receptora u WO91/09594 i WO 93/00313, koji ima neki utjecaj na 3,4-dihidroksifeniloctenu kiselinu u striatumu; 852 ± 33 (nadzori) na 1406 ± 77 ng/g tkiva kod 50 µmola/kg s.c., p < 0,05, n = 4, ali također smanjuje oba i 5-hidroksiindoloctenu kiselinu u striatumu od 358 ± 20 (nadzori) na 289 ± 16 ng/g tkiva kod 50 µmola/kg s.c., p < 0,05, n = 4, i serotonin (5-HT) od 379 ± 10 (nadzori) na 282 ± 6 ng/g tkiva kod 50 µmola/kg s.c., p < 0,05, n = 4, što je neželjeno svojstvo prema ovom izumu ali u skladu s izvještenim IC50 od 20,3 nM na 5-HT1A receptoru (WO 93/00313).
Usporedni primjer 9: Dodatno, 1-benzil-4-(3-metansulfonil-fenil)-piperidin i 3-(1-benzil-piperidin-4-il)-fenol, spojevi s benzenskom supstitucijom na bazičnom dušiku, oba imaju neželjeno svojstvo da reagiraju sa serotoninskim sustavima u mozgu. 1-Benzil-4-(3-metansulfonil-fenil)-piperidin povećava 5-hidroksiindoloctenu kiselinu u striatumu od 428 ± 20 (nadzori) na 487 ± 7 ng/g tkiva kod 50 µmola/kg s.c., p < 0,05, n = 4, a smanjuje serotonim (5-HT) od 442 ± 15 (nadzori) na 345 ± 18 ng/g tkiva kod 50 µmola/kg s.c., p < 0,05, n = 4, i inducira sindrom serotoninskog ponašanja (sindrom serotoninskog ponašanja je, na primjer, opisan od Tricklebanka i ostalih, 1985., Eur. J. Pharmacol., 106, str. 271-282).
3-(1-Benzil-piperidin-4-il)-fenol ima neželjenu mogućnost povećanja 5-hidroksiindoloctene kiseline u striatumu od 404 ± 10 (nadzori) na 492 ± 26 ng/g tkiva kod 50 µmola/kg s.c., p < 0,05, n = 4, a smanjuje serotonin u području udova (5-HT) od 734 ± 8 (nadzori) na 677 ± 20 ng/g tkiva kod 50 µmola/kg s.c., p < 0,05, n = 4.
Usporedni primjer 10: Supstitucija bazičnog dušika u 2-[4-(3-metansulfonil-fenil)-piperazin-1-il]-etanol] (opisano u GB 2027703) zadržava spojeve koji su neaktivni u testu aktivnosti ponašanja; 3238 ± 1089 cm/60 min (nadzori) na 3782 ± 962 cm/60 min kod 33 µmola/kg s.c., n = 4, p > 0,05, kao i kod neurokemijskog testa; učinci na 3,4-dihidroksifeniloctenu kiselinu u striatumu; 1158 ± 126 (nadzori) na 1239 ± 162 ng/g tkiva kod 33 µmola/kg s.c., n = 4, p > 0,05.
Spojevi prema izumu su osobito pogodni za tretiranje poremećaja u središnjem živčanom sustavu, i posebno za tretiranje poremećaja povezanih s dopaminom. Oni se mogu, na primjer, koristiti za smanjenje simptoma poremećaja raspoloženja, kod debljine kao anorektičko sredstvo i kod ostalih poremećaja jedenja, za poboljšanje kognitivnih funkcija i odgovarajućih emocionalnih poremećaja, za poboljšanje kognitivnih i motoričkih nefunkcioniranja povezanih s poremećajima u razvoju, za poboljšanje svih simptoma šizofrenije i šizofreničkih poremećaja, kao i ostalih psihoza, za poboljšanje simptoma u tijeku kao i za spriječavanje pojave novih psihotičkih epizoda, za reguliranje patoloških poremećaja uzrokovanih uzimanjem hrane, kave, čaja, duhana, alkohola, adiktivnih lijekova itd.
Spojevi prema izumu se stoga mogu koristiti za tretiranje simptoma kod, na primjer:
- šizofrenije i ostalih psihotičkih poremećaja, kao što je katatonija, neorganiziranost, paranoja, rezidualna ili diferencirana šizofrenija; šizofrenoidni poremećaj; šizoafektivni poremećaj; poremećaj s priviđenjima; kratki psihotički poremećaj; dijeljeni psihotički poremećaj; psihotički poremećaj uzrokovan općim medicinskim stanjem s priviđenjima i/ili halucinacijama;
- poremećaja raspoloženja, kao što su depresivni poremećaji, na primjer, distimički poremećaj ili glavni depresivni poremećaj; bipolarni poremećaji, na primjer, bipolarni I poremećaj, bipolarni II poremećaj i ciklotimički poremećaj; poremećaj raspoloženja radi općeg medicinskog stanja s depresivnim i/ili maničkim obilježima; i tvarima induciranim poremećajem raspoloženja;
- poremećaji nespokojstva, kao što su akutni stresni poremećaj, agorafobija bez povijesti paničnog poremećaja, poremećaj nespokojstva radi općeg medicinskog stanja, uopćeni poremećaj nespokojstva, opsesivno-kompulzivni poremećaj, panični poremećaj s agorafobijom, panični poremećaj bez agorafobije, posttraumatski stresni poremećaj, specifična fobija, socijalna fobija i tvarima inducirani poremećaj nespokojstva;
- poremećaji kod jela, kao što je nervozna anoreksija, nervozna bulimija i prekomjerna težina;
- poremećaji spavanja, kao što je disomnija, na primjer, poremećaj spavanja povezan s disanjem, poremećaj spavanja cirkadijanskog ritma, hipersomnija, insomnija, narkolepsija i «jet lag»;
- poremećaji nadzora impulsa koji nisu drugdje svrstani, kao što je povremeni eksplozivni poremećaj, kleptomanija, patološko kockanje, piromanija i trihotilomanija;
- poremećaji osobnosti, kao što je paranoja, šizoidni ili šizotipični poremećaj; antisocijalni, granični, histrionični i narcisoidni poremećaj; i dokinuti, ovisan, opsesivno-kompulzivni poremećaj;
- lijekovima inducirani poremećaji pokretanja, kao što su neuroleptički inducirani parkinsonizam, neuroleptički maligni sindrom, neuroleptička inducirana akutna i tardivna distonija, neuroleptička inducirana akatizija, neuroleptička inducirana tardivna diskinezija, drhtanje inducirano lijekovima i diskinezije inducirane lijekovima;
- tvarima povezani poremećaji, kao što su zlouporaba, ovisnost, poremećaj potištenosti, trovanje, delirij zbog trovanja, psihotički poremećaj, psihotički poremećaj s izmišljanjima, poremećaj raspoloženja, poremećaj ustrajne amnestije, ustrajna demencija, ustrajni poremećaj percepcije, seksualno nefunkcioniranje, poremećaj spavanja, prestanak uzimanja i delirij zbog prestanka uzimanja ili zlouporabe zbog uporabe alkohola, amfetamina (ili amfetaminu slične tvari), kafeina, marihuane, kokaina, halucinatora, inhalanata, nikotina, opioida, fenilciklidina (ili fenilciklidinu sličnih tvari, sedativa, hipnotika i/ili tvari koje izazivaju tjeskobu;
- poremećaji obično prvo dijagnosticirani u ranom djetinjstvu, djetinjstvu i mladenačkoj dobi, kao što je mentalna retardiranost; poremećaji učenja; poremećaji motorike, na primjer poremećaj razvoja koordinacije; poremećaji komuniciranja, na primjer poremećaj govorenja, fonološki poremećaj, poremećaj poimanja govorenja i mucanje; poremećaji pervazivnog razvoja, na primjer Aspergerov poremećaj; autistični poremećaj, poremećaj disintegrativnog djetnjstva i Rettov poremećaj; pomanjkanje pažnje i poremećaji disruptivnog ponašanja, na primjer poremećaj manjka pažnje/hiperaktivnost, poremećaj vođenja i poremećaj drskog oponiranja; poremećaj hranjenja i jedenja u ranom djetinjstvu ili djetinjstvu, pica, poremećaj preživanja; tikovi, na primjer kronični poremećaj motoričkog ili glasovnog tika i Tuorettov poremećaj; ostali poremećaji ranog djetinjstva, djetinjstva ili mladenačke dobi, na primjer selektivno mutiranje i poremećaj stereotipnog pokretanja;
- delirijum, demencija, amnestički i drugi kognitivni poremećaji, kao što su Alzheimer, Creutzfeldt-Jakobovo oboljenje, trauma zbog smrti, Huntingtonovo oboljenje, HIV, Pickovo oboljenje i difuzna Lewyjeva tjelesna demencija;
- konverzijska histerija;
- stanja povezanja s normalnim starenjem, kao što su poremećaj motoričkih funkcija i mentalnih funkcija;
- Parkinsonovo oboljenje i povezani poremećaji, kao što su višestruka sustavna atrofija, na primjer striatonigralna degeneracija, olivopontocelebralna atrofija i šidragerov sindrom; progresivna supranuklearna uzetost; kortikobazalna degeneracija i vaskularni parkinsonizam;
- podrhtavanja, kao što su esencijalna, ortostatička, odmor, cerebelarna i sekundarna podrhtavanja;
- glavobolje, kao što su migrena, grozdasta glavobolja, glavobolja tenzijske vrste i paroksismalna glavobolja;
- poremećaji pokretanja, kao što su diskinezije, na primjer kod skrivenog medicinskog stanja, sekundarno nakon traume ili vaskularnog udara, hemibalizam, atetoze, Sydenhamova koreja i paroksismal; distonije; Ekbomov sindrom (nemirne noge); Wilsonovo oboljenje, Hallerworden-Spatzovo oboljenje;
- rehabilitacijska medicina, na primjer poboljšanje rehabilitacije nakon vaskularne ili traumatske povrede mozga;
- bol u stanjima karakteriziranim povećanim mišićnim tonusom, kao što su fibromialgija, miofascijalni sindrom, distonija i parkinsonizam; kao i
- stanja povezana s gornjim koja upadaju u veće kategorije ali se ne poklapaju kriteriji bilo kojeg specifičnog poremećaja unutar tih kategorija.
Sinteza
Sinteza sadašnjih spojeva se provodi načinima koji su uobičajeni za sintezu povezanih poznatih spojeva. Sinteza spojeva u Formuli 1, općenito, obuhvaća reakciju nekog međuspoja koji donosi alkilnu skupinu s piperidinskim međuspojem ili piperazinom koji nosi amino skupinu Formule 2:
[image]
Uobičajeni način sinteze sadašnjih spojeva je uporabom nekog alkilnog jodida (na primjer 1-propil-jodida). Alternativno se naravno mogu koristiti druge odlazeće skupine osim jodida na alkilnoj skupini, kao što su sulfonati, osobito metansulfonat ili toluensulfonat, brom i slične. Alkilni međuspoj reagira s odgovarajućim aminom u nazočnosti bilo kojeg sredstva za uklanjanje kiseline. Uobičajene baze kao što su alkalne kovine ili alkalni zemnokovinski karbonati, bikarbonati i hidroksidi su korisna sredstva za uklanjanje, kao što su i neke organske baze kao što su trialkilamini i trialkanolamini. Reakcijska sredina za takve reakcije može biti bilo koje uobičajeno organsko otapalo koje je inertno u baznim uvjetima; korisni su acetonitril, esteri kao što je etilni acetat i slični i halogenirana alkalna otapala. Uobičajeno će se reakcije provoditi kod povišenih temperatura kao što su od temperature okoline do temperature refluksa reakcijske smjese, osobito od 50 ̊C do oko 100 ̊C.
Drugi uobičajeni način sinteze sadašnjih spojeva uključuje reduktivnu aminaciju s aminom Formule 2:
[image]
s aldehidom ili ketonom, bilo u nazočnosti reducirajućeg sredstva kao što je natrijev cijanoborhidrid ili natrijev triacetoksiborhidrid ili nakon redukcije, na primjer uporabom katalitičkog hidriranja, da bi dao odgovarajući spoj formule 1.
Spoj Formule 3
[image]
gdje je X=N je postignut reakcijom spojeva Formule 4 :
[image]
sa spojevima Formule 5 :
[image]
gdje je Z odlazeća skupina kao jodid. Naravno da se mogu koristiti druge odlazeće skupine osim jodida na alkilnoj skupini, kao što su sulfonati, osobito metansulfonat ili toluensulfonat, brom i slične. Alkilni međuspoj reagira s odgovarajućim aminom u nazočnosti bilo kojeg sredstva za uklanjanje kiselina. Uobičajene baze kao što su alkalne kovine ili alkalni zemnokovinski karbonati, bikarbonati i hidroksidi su korisni kao takva sredstva, kao što su i neke organske baze kao što su trialkilamini i trialkanolamini. Reakcija je provedena u pogodnom otapalu kao što je n-butanol grijanjem kod oko 50-150 ̊C.
Spojevi Formule 1 gdje je X = N je također postignut reakcijom spojeva Formule 6 :
[image]
s nekim arilom koji je supstituiran s odlazećom skupinom Formule 7 :
[image]
gdje je Z halid, na primjer klor, brom, jod ili sulfonat, na primjer -OSO2CF3 ili -OSO2F, u nazočnosti baze i nulavalentnog prelaznog kovinskog katalizatora kao što su Pd ili Ni, prema poznatim načinima (Tetrahedron Letters, vol. 37, 1996., 4463-4466, J. Org. Chem., vol. 61, 1996., 1133-1135).
Katalizator, poželjno Pd će biti sposoban načiniti kompleksni ligand i podvrći se oksidativnoj adiciji. Tipični Pd katalizatori će biti Pd2(dba)3 (gdje se dba odnosi na di-benziliden aceton), Pd(PPh3)4, Pd(OAc)2 ili PdCl2[P(o-tol)3]2 i tipični fodfinski ligandi će biti BINAP, P(o-tol)3, dppf ili slični. Uobičajene baze kao što su alkalne kovine ili alkalni zemnokovinski karbonati, bikarbonati i hidroksidi su korisni kao sredstva za uklanjanje kiseline, kao što su i neke organske baze kao što su trialkilamini i trialkanolamini. Reakcijska sredina za takve reakcije može biti bilo koje uobičajeno organsko otapalo koje je inertno u baznim uvjetima; korisna otapala su acetonitril, toluen, dioksan, NMP (N-metil-2-pirolidon), DME (dimetoksietan), DMF (N,N-dimetilformamid), DMSO (dimetilsulfoksid) i THF (tetrahidrofuran). Uobičajeno će se reakcije provoditi kod povišenih temperatura kao što su od temperature okoline do temperature refluksa reakcijske smjese, osobito od 50 ̊C do oko 120 ̊C.
Spojevi Formule 1 gdje je X = N su također dobiveni reakcijom spojeva Formule 6 s nekim arilom supstituiranim s odlazećom skupinom (na primjer F ili Cl) preko reakcije nukleofilne aromatske zamjene u nazočnosti baze kako je objašnjeno gore.
Spojevi Formule 1 gdje je X = CH su također dobiveni reakcijom unakrsnog vezanja kataliziranog prelaznom kovinom, poznatom kao, na primjer, Suzuki i Stille reakcijama, za one iskusne u području.
Reakcija se može provesti između spojeva Formule 8 :
[image]
gdje je Y, na primjer, dialkilboran, dialkenilboran ili boronična kiselina (na primjer BEt2, B(OH)2 (točkaste crte mogu biti dvostruke veze)) ili trialkilkositar (na primjer SnMe3, SnBu3) i neki aril supstituiran s odlazećom skupinom Formule 7 :
[image]
(za definiciju Z, vidi gore) u nazočnosti baze i katalizatora koji je nulavalentna prelazna kovina kao što su Pd i Ni, prema poznatim načinima (Chem. Pharm. Bull., vol. 33, 1985., 4755-4763, J. Am. Chem. Soc., vol. 109, 1987., 5478-5486., Tetrahedron Lett., vol. 33, 1992., 2199-2202). Dodatno, Y također može biti cink- ili magnezij-halid (na primjer ZnCl2, ZnBr2, ZnI2, MgBr2, MgI2) prema poznatim načinima (Tetrahedron Lett., vol. 33, 1992., 5373-5374, Tetrahedron Lett., vol. 37, 1996., 5491-5494).
Katalizator, poželjno Pd će moći načiniti kompleksni ligand i podlijegati oksidativnoj adiciji. Definicija liganada, baza i otapala je spomenuta gore.
Na drugi način, reakcija unakrsnog vezivanja katalizirana prelaznom kovinom može se provesti kao nasuprotna supstitucija :
[image]
s nekim heteroarilom/alkenilom supstituiranim s odlazećom skupinom Formule 10 :
[image]
u nazočnosti baze i nulavalentnog katalizatora prelazne kovine kao što su Pd ili Ni, prema poznatim načinima diskutiranim u prethodnom odlomku.
Spojevi Formule 11 :
[image]
mogu se pripraviti katalitičkim hidriranjem tetrahidropiridina ili piridina iz ranijeg odlomka, uporabom uobičajenih načina poznatih u području, općenito s paladijem na ugljenu, PtO2 ili Raney niklom kao katalizatorom. Reakcija se provodi u inertnom otapalu, kao što su etanol ili etilni acetat, bilo bez ili sa protičnom kiselinom, kao što je octena kiselina ili HCl. Kada je piridinski prsten kvarteniziran s alkilnom skupinom prsten se može djelomično reducirati s NaBH4 ili NaCNBH4, dajući tetrahidropiridinski analog koji se može dalje reducirati katalitičkim hidriranjem.
Drugi odgovarajući način sinteza spojeva Formule 1, gdje je X = CH je također načinjen tretiranjem arilhalida Formule 7 :
[image]
gdje je Z Cl, Br ili I, s alkillitijevim reagensima, na primjer butillitijem, sec-butillitijem ili tert-butillitijem, poželjno butillitijem ili Mg (Grignardova reakcija) u inertnom otapalu. Pogodna otapala uključuju, na primjer eter ili tetrahidrofuran. Raspon temperatura reakcije je od oko -110°C do oko 60°C. Intermedijarni litijevi anioni ili magnezijevi anioni tako nastali mogu dalje reagirati s pogodnim elektrofilom formule 12 :
[image]
gdje je A određen kao zaštitna skupina poput t-Boc (tert-butoksikarbonil), Fmoc (fluorenilmetoksikarbonil), Cbz (benziloksikarbonil) ili neka alkilna skupina kao benzil.
Međuspojevi Formule 13 :
[image]
koji su nastali zahtjevaju da se hidroksilna skupina ukloni tako da nastanu spojevi Formule 1 (X=CH).
Ovaj stupanj može biti načinjen na jedan od nekoliko standardnih načina poznatih u području. Na primjer, tiokarbonilni derivat (na primjer ksantat) se može pripraviti i ukloniti postupkom slobodnog radikala, koji je poznat onima koji su iskusni u području. Na drugi način se hidroksilna skupina može ukloniti redukcijom s izvorom hidrida kao što je trietilsilan u kiselin uvjetima, koristeći, na primjer, trifluoroctenu kiselinu ili bor trifluorid. Reakcija redukcije se može provesti bez ili u otapalu, kao što je metilen klorid. Daljnja alternativa bi bila prvo pretvoriti hidroksilnu skupinu u pogodnu odlazeću skupinu, kao što je tosilat ili klorid, uporabom standardnih načina. Odlazeća skupina se tada uklanja s nukleofilnim hidridom, kao što je, na primjer, litijev aluminijev hidrid. Ova zadnja reakcija se tipično provodi u inertnom otapalu, kao što je eter ili tetrahidrofuran.
Drugi alternativni način za uklanjanje hidroksilne skupine je prvo dehidrirati alkohol u neki olefin s reagensom kao što je Burgessova sol (J. Org. Chem., vol. 38, 1973., 26) nakon čega slijedi katalitičko hidriranje dvostruke veze uz standardne uvjete s katalizatorom kao što je paladij na ugljenu. Alkohol se također može dehidrirati u olefin tretiranjem s kiselinom kao što je p-toluensulfonska kiselina ili trifluoroctena kiselina.
Zaštitna skupina A je uklonjena pod standardnim uvjetima poznatim onima iskusnim u području. Na primjer, skidanje t-Boc skupine se uobičajeno provodi s trifluoroctenom kiselinom bilo bez bilo skupa s metilen kloridom. F-moc skupina se uobičajeno skida s jednostavnom bazom kao što je amonijak, piperidin ili morfolin, obično u polarnim otapalima kao što su DMF i acetonitril. Kada je A Cbz ili benzil, oni se uobičajeno uklanjaju u uvjetima katalitičkog hidriranja. Benzilna skupina se također može ukloniti u uvjetima N-dealkilacije kao što je tretiranje s α-kloretil klorformatom (J. Org. Chem., vol. 49, 1984., 2081-2082).
Dalje je moguće prevesti radikal R1 u spoju Formule 1 u neki drugi radikal R1, na primjer s m-klorperoksibenzojevom kiselinom), supstitucijom triflatne ili halidne skupine s cijano skupinom (na primjer paladijem kataliziranom cijanacijom), supstitucijom triflatne ili halidne skupine s ketonom (na primjer paladijem katalizirana Heckova reakcija s butil vinil eterom), supstitucijom triflatne ili halidne skupine s karboksamidom (na primjer paladijem katalizirana karbonilacija) ili odcjepljenjem etera s, na primjer, pretvorbom metoksilne skupine u odgovarajući hidroksilni derivat, koji se dalje može pretvoriti u odgovarajući mesilat ili triflat. Pojmovi mesilat i triflat se odnose na OSO2CH3, CH3SO3 ili OSO2CF3, odnosno CF3SO3.
Zbirno, općeniti postupak za pripravu sadašnjih spojeva ima šest glavnih inačica, koje se mogu ukratko opisati kako slijedi:
prema Shemi 1 :
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X = N, CH ili C X = N, CH ili C
ili prema Shemi 2 :
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X = N, CH ili C (Y = neovisno H X = N, CH ili C
ili male alkilne
skupine)
ili prema Shemi 3 :
[image]
ili prema Shemi 4 :
[image]
ili prema Shemi 5 :
[image]
ili prema Shemi 6 :
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Kako se ovdje koristi, izraz C1-C4 alkil se odnosi na neki alkil koji sadrži 1-4 ugljikova atoma u bilo kojem izomernom obliku. Različite ugljikove molekule su određene kako slijedi: alkil se odnosi na neki alifatski ugljikovodični radikal i uključuje razgranate i nerazgranate oblike kao što su, metil, etil, n-propil, i-propil, n-butil, i-butil, s-butil, t-butil. Izraz cikloalkil se odnosi na radikal zasićenog ugljikovodika kao što je ciklopropil, ciklobutil, ciklopentil, cikloheksil.
Izraz ̋pacijent ̋ korišten ovdje se odnosi na nekog pojedinca koji treba tretiranje prema sadašnjem izumu.
Izraz ̋tretiranje ̋ korišten ovdje odnosi se i na tretiranje u cilju liječenja ili umanjenja oboljenja ili stanja, i na tretiranje u cilju spriječavanja razvoja oboljenja ili stanja. Tretiranje se može izvesti bilo akutno ili kronično.
I organske i anorganske kiseline se mogu upotrebljavati za nastajanje neotrovnih farmaceutski prihvatljivih kiselinskih adicijskih soli spojeva prema izumu. Ilustrativne kiseline su sumporna, dušična, fosforna, klorovodična, limunska, octena, mliječna, vinska, palmitinska, etan disulfonska, sulfaminska, jantarna, cikloheksilsulfaminska, fumarna, maleinska i benzojeva kiselina. Ove soli se lagano pripravljaju načinima poznatim u području.
Farmaceutski pripravci koji sadrže spoj prema izumu mogu također obuhvaćati tvari koje se koriste za olakšanje proizvodnje farmaceutskih pripravaka ili davanje pripravaka. Takve tvari su dobro poznate ljudima iskusnim u području i mogu na primjer biti farmaceutski prihvatljivi adjuvanti, nosači i konzervansi.
U kliničkoj praksi će se spojevi koji se koriste prema sadašnjem izumu normalno davati oralno, rektalno ili injekcijama, u obliku farmaceutskih pripravaka koji obuhvaćaju aktivni sastojak bilo kao slobodnu bazu ili kao farmaceutski prihvatljivu neotrovnu, kiselinsku adicijsku sol, kao što su hidroklorid, laktat, acetat, sulfamat, skupa s farmaceutski prihvatljivim nosačem. Nosač može biti kruti, polukruti ili tekući pripravak Uobičajeno će aktivna tvar činiti između 0,1 i 99% težinski pripravka, specifičnije između 0,5 i 20% težinski za pripravke koji su namijenjeni za injekcije i između 0,2 i 50% težinski za pripravke pogodne za oralno davanje.
Radi proizvodnje farmaceutskih pripravaka koji sadrže spoj prema izumu u obliku jediničnih doza za oralnu primjenu, odabrani spoj se može miješati s krutim dodacima, na primjer laktozom, saharozom, sorbitolom, manitolom, škrobovima kao što su krumpirov škrob, kukuruzni škrob ili amilopektin, derivatima celuloze, vezivima kao što su želatina ili polivinil-pirolidon, podmazivačima kao što su magnezijev stearat, kalcijev stearat, polietilen glikol, voskovi, parafin i slični, i tada se stlačiti u tablete. Ukoliko se traže prevučene tablete, jezgre, pripravljene kako je opisano gore, se mogu prevuči s koncentriranom otopnom šećera koja može sadržavati gumiarabiku, želatinu, milovku, titanov dioksid i slično. Na drugi način se tablete mogu prevuči s polimerom poznatim ljudima iskusnim u području, otopljenim u lako hlapivom organskom otapalu ili smjesi organskih otapala. Bojila se mogu dodati ovim prevlakačima s ciljem lakog razlikovanja između tableta koje sadrže različite aktivne tvari ili različite količine aktivnog spoja.
Za pripravu mekih želatinskih kapsula, aktivna tvar se može pomiješati s na primjer biljnim uljem ili polietilen glikolom. Tvrde želatinske kapsule mogu sadržavati zrnca aktivne tvari uporabom bilo spomenutih dodataka za tablete, na primjer laktoze, saharoze, sorbitola, manitola, škrobova (na primjer krumpirovog škroba, kukuruznog škroba ili aminopektina), derivata celuloze ili želatine. U tvrde želatinske kapsule se mogu također puniti tekućine ili polukruti lijekovi.
Jedinične doze za rektalnu primjenu mogu biti otopine ili suspenzije ili se mogu pripraviti u obliku supozitorija koji obuhvaćaju aktivnu tvar u smjesi s neutralnim masnim bazama, ili želatinskim rektalnim kapsulama koje obuhvaćaju aktivnu tvar pomiješanu s biljnim uljem ili parafinskim uljem. Tekući pripravci za oralnu primjenu mogu biti u obliku sirupa ili suspenzija, na primjer otopine koje sadržavaju od oko 0,2% do oko 20% težinski aktivne tvari ovdje opisane, razlika je šećer ili smjesa etanola, vode, glicerina i propilen glikola. Po izboru takvi tekući pripravci mogu sadržavati sredstva za bojenje, sredstva za okus, saharin i karboksimetilcelulozu kao sredstvo za zgušnjavanje ili ostale dodatke poznate čovjeku u području.
Otopine za parenteralne primjene s injekcijama se mogu pripraviti u vodenoj otopini u vodi topivih farmaceutski prihvatljivih soli aktivne tvari, poželjno u koncentracijama od 0,5% do oko 10% težinski. Ove tekućine također mogu sadržavati sredstva za stabilizaciju i/ili pufere i mogu biti osigurani u različitim ampulama jediničnih doza. Uporaba i davanje pacijentu koji će se tretirati klinički bit će očiti iskusnom u području.
Kod terapijskog tretiranja neka djelotvorna količina ili terapijska količina spojeva prema izumu je od oko 0,01 do oko 500 mg/kg tjelesne težine dnevno, poželjno 0,1-10 mg/kg tjelesne težine dnevno. Spojevi se mogu davati na bilo koji pogodan način, kao što je oralno ili paranteralno. Dnevna doza će se poželjno davati u pojedinačnim dozama 1 do 4 puta dnevno.
Onima iskusnima u području je poznato da zamjena vodika u nesupstituiranom položaju aromatskog prstena s atomom fluora može zakočiti mogućnost enzimatske hidroksilacije što zadržava nisku oralnu biodostupnost spoja. Ova vrsta zamjene (H za F) rijetko mijenja farmakološki profil. Stoga može biti važno, u nekim slučajevima, uvesti atom fluora u bilo koji nesupstituirani položaj na aromatskom prstenu spojeva Formule 1 radi poboljšanja oralne biodostupnosti.
Izum je dalje prikazan u primjerima ispod, koji ni na koji način nemaju namjeru ograničiti doseg izuma.
Primjer 1: 1-(3-Metansulfonil-fenil)-4-propil-piperazin
Suspenzija 1-(3-metansulfonil-fenil)-piperazina (350 mg) i zdrobljenog K2CO3 (403 mg) je miješana u CH3CN (25 mL) kod sobne temperature. Dodan je 1-jod-propan (712 µL). Smjesa je refluktirana preko noći. Reakcijska smjesa je filtrirana i hlapivi sastojci su upareni u vakuumu. Uljasti ostatak je kromatografiran an stupcu silikagela s MeOH:CH2Cl2 (1:30 volumski) kao eluensom. Skupljanjem frakcija koje sadrže čisti produkt i uparavanjem otapala se dobio čisti 1-(3-metansulfonil-fenil)-4-propil-piperazin (220 mg). Amin je preveden u HCl sol i prekristaliziran iz etanol/dietiletera: t.t. 233 ̊C MS m/z (relativni intenzitet, 70 eV) 282 (M+, 30), 254 (15), 253 (bp), 210 (17), 70 (21).
Slijedeći spojevi prema Primjerima 2 - 11 su pripravljeni na način sličan onom opisanom u Primjeru 1.
Primjer 2: 1-Propil-4-(3-trifluormetansulfonil-fenil)-piperazin
MS m/z (relativni intenzitet, 70 eV) 336 (M+, 16), 307 (bp), 77 (18), 70 (38), 56 (23).
Primjer 3: 1-[3-(4-Propil-piperazin-1-il)-fenil]-etanon
Počevši s 1-(3-piperazin-1-il-fenil)-etanonom i n-Pr-I: t.t. 119 ̊C (oksalat), MS m/z (relativni intenzitet, 70 eV) 246 (M+, 10), 217 (33), 132 (18), 70 (bp), 56 (41); Rf 0,23 (EtOAc).
Primjer 4: 1-Propil-4-(3-trifluormetil-fenil)-piperidin
Počevši s 4-(3-trifluormetil-fenil)-piperidinom i n-Pr-I: t.t. 195 ̊C (HCl), MS m/z (relativni intenzitet, 70 eV) 271 (M+, 4), 243 (16), 242 (bp), 159 (13), 70 (49).
Primjer 5: 1-Butil-4-(3-trifluormetil-fenil)-piperidin
Počevši s 4-(3-trifluormetil-fenil)-piperidinom i n-Bu-Br: t.t. 222 ̊C (HCl), MS m/z (relativni intenzitet, 70 eV) 285 (M+, 3), 243 (12), 242 (bp), 70 (51), 56 (17).
Primjer 6: 4-(3-Metansulfonil-fenil)-1-propil-piperidin
t.t. 200 ̊C (HCl), MS m/z (relativni intenzitet, 70 eV) 281 (M+, 5), 252 (bp), 129 (20), 115 (20), 70 (25).
Primjer 7: 4-(3-Metansulfonil-fenil)-1-propil-1,2,3,6-tetrahidro-piridin
Počevši s 4-(3-metansulfonil-fenil)-1,2,3,6-terahidro-piridinom i jodpropanom: MS m/z (relativni intenzitet, 70 eV) 279 (M+, 26), 250 (bp), 171 (6), 128 (12), 115 (8).
Primjer 8: 4-(3-Metansulfonil-fenil)-1-etil-piperidin
Počevši s 4-(3-metansulfonil-fenil)-piperidinom i jodetanom : t.t. 158 ̊C (HCl). MS m/z (relativni intenzitet, 70 eV) 267 (M+, 20), 252 (bp), 130 (10), 115 (12), 84 (20);
Primjer 9: 1-Izopropil-4-(3-metansulfonil-fenil)-piperidin
Počevši s 4-(3-trimetansulfonil-fenil)-piperidinom i i-propilbromidom: t.t. 220 ̊C (HCl); MS m/z (relativni intenzitet, 70 eV) 281 (M+, 4), 266 (bp), 187 (5), 129 (5), 115 (5).
Primjer 10: 4-(3-Metansulfonil-fenil)-1-butil-piperidin
Počevši s 4-(3-metansulfonil-fenil)-piperidinom i n-Bu-Cl. MS m/z (relativni intenzitet, 70 eV) 295 (M+, 3), 252 (bp), 130 (5), 115 (3), 70 (8).
Primjer 11: 1-Izobutil-4-(3-metansulfonil-fenil)-piperidin
Počevši s 4-(3-metansulfonil-fenil)-piperidinom i i-butilbromidom: t.t. 212 ̊C (HCl), MS m/z (relativni intenzitet, 70 eV) 295 (M+, 1), 252 (80), 129 (40), 115 (50), 70 (bp).
Primjer 12: 3-(1-Propil-piperidin-4-il)-benzonitril
Otopina 3-(1-propil-piperidin-4-il)-benzamida (350 mg) i POCl3 (326 µL) u suhom DMF (6 mL) je grijano kod 80 ̊C kroz 3 h u atmosferi argona. Uparavanje otapala je dalo tamni uljasti ostatak, koji je otopljen u vodi. Otopina je zalužena i ekstrahirana s CH2Cl2. Skupljeni organski dijelovi su sušeni (MgSO4), filtrirani i upareni. Uljasti ostatak je kromatografiran na stupcu silikagela s MeOH:CH2Cl2 (1:19 (volumski)) kao eluensom. Skupljanje frakcija koje sadrže čisti produkt i uparavanjem otapala se dobio čisti 3-(1-propil-piperidin-4-il)-benzonitril (127 mg). Amin je preveden u sol fumarne kiseline i prekristaliziran iz etanol/dietiletera: t.t. 122 ̊C; MS m/z (relativni intenzitet, 70 eV) 228 (M+, 2), 199 (42), 129 (26), 70 (bp), 56 (53).
Primjer 13: 1-sec-Butil-4-(3-metansulfonil-fenil)-piperidin
4-(3-Metansulfonil-fenil)-piperidin hidroklorid (20 mg), ledena octena kiselina (4,4 mg) i 2-butanon (5,1 mg) su pomiješani u 1,2-dikloretanu (5 mL). Dodan je natrijev triacetoksiborhidrid (23,5 mg) u otopinu i reakcijska smjesa je miješana kod sobne temperature u atmosferi dušika kroz 5 h (G.L.C. analiza je ukazivala da je reakcija okončana). Reakcija je prekinuta sa zasićenom vodenom otopinom NaHCO3, produkt je ekstrahiran s CH2Cl2. Skupljeni organski dijelovi su sušeni (MgSO4), filtrirani i otapalo je upareno da bi se dobio 1-sec-butil-4-(3-metansulfonil-fenil)-piperidin kao uljasti ostatak. Produkt je kromatografiran na stupcu silikagela s CH2Cl2:MeOH (9:1 (volumski)) kao eluensom. Skupljanje frakcija koje sadržavaju čisti produkt i uparavanje otapala je dalo čisti amin (15 mg, 71%); MS m/z (relativni intenzitet, 70 eV) 295 (M+, 1), 280 (7), 266 (bp), 187 (4), 129 (4).
Primjer 14: Metansulfonska kiselina 3-(1-propil-piperidin-4-il)-fenil ester
Otopina 3-(1-propil-piperidin-4-il)-fenola (340 mg) i trietilamina (187 mg) u 20 mL CH2Cl2 je ohlađena na 0 ̊C. Tada je dokapan metansulfonil klorid (194 mg) otopljen u 10 mL CH2Cl2. Reakcijska smjesa je puštena da postigne sobnu temperaturu i tada je miješana kroz 2,5 h kod 25 ̊C. Reakcija je konačno prekinuta s vodom. Organski sloj je odijeljen i ispran s 10%-tnom HCl i zatim s 10%-tnim Na2CO3.
Nakon sušenja (MgSO4) je otapalo uklonjeno uz smanjeni tlak. Ostatak je kromatografiran na stupcu silikagela korištenjem MeOH: CH2Cl2 (1:9 (volumski)) kao eluensa. Frakcije koje su sadržavale čistu metansulfonsku kiselinu 3-(1-propil-piperidin-4-il)-fenil ester su skupljene i otapalo je uklonjeno u vakuumu, dajući 206 mg naslovnog spoja. (MS m/z (relativni intenzitet, 70 eV) 297 (M+, 3), 268 (bp), 189 (24), 131 (13), 79 (16);
Slijedeći spojevi u Primjerima 15-19 su pripravljeni na način sličan onom opisanom u Primjeru 14.
Primjer 15: Metansulfonska kiselina 3-(1-etil-piperidin-4-il)-fenil ester
Počevši s 3-(1-etil-piperidin-4-il)-fenolom i metansulfonil kloridom. MS m/z (relativni intenzitet, 70 eV) 283 (M+, 6), 268 (bp), 189 (54), 131 (20), 79 (70);
Primjer 16: Metansulfonska kiselina 3-(1-butil-piperidin-4-il)-fenil ester
Počevši s 3-(1-butil-piperidin-4-il)-fenolom i metansulfonil kloridom. MS m/z (relativni intenzitet, 70 eV) 311 (M+, 3), 268 (bp), 189 (20), 131 (18), 79 (12);
Primjer 17: Metansulfonska kiselina 3-(4-propil-piperidin-1-il)-fenil ester
Počevši s 3-(4-propil-piperidin-1-il)-fenolom i metansulfonil kloridom: t.t. 143-144 ̊C (fumarat); MS m/z (relativni intenzitet, 70 eV) 298 (M+, 35), 269 (95), 121 (25), 84 (30), 70 (bp);
Primjer 18: Trifluor-metansulfonska kiselina 3-(1-propil-piperidin-4-il)-fenil ester
Počevši s 3-(1-propil-piperidin-4-il)-fenolom i anhidridom trifluormetansulfonske kiseline MS m/z (relativni intenzitet, 70 eV) 351 (M+, 4), 322 (65), 189 (30), 131 (20), 69 (bp).
Primjer 19: Trifluor-metansulfonska kiselina 3-(1-etil-piperidin-4-il)-fenil ester
Počevši s 3-(1-etil-piperidin-4-il)-fenolom i anhidridom trifluormetansulfonske kiseline MS m/z (relativni intenzitet, 70 eV) 337 (M+, 4), 322 (65), 189 (30), 131 (20), 69 (bp).
Primjer 20: 1-[3-(1-Propil-piperidin-4-il)-fenil]-etanon
Miješanoj otopini trifluor-metansulfonske kiseline 3-(1-propil-piperidin-4-il)-fenil estera (300 mg) u DMF ( 4 mL) u atmosferi argona kod sobne temperature su jedan za drugim dodavani NEt3 (356 µL), butil vinil eter (823 µL), 1,3-bis(difenilfosfino)propan (50 mg) i Pd(OAc)2 (19 mg). Reakcijska smjesa je tada grijana na 80 ̊C i nakon 2 h je reakcija zaustavljena. Dodana je 5%-tna otopina hidrokloridne kiseline (6 mL) i skupljena smjesa je miješana kroz 45 min. Tada je dodan CH2Cl2. Skupljeni organski dijelovi su sušeni (MgSO4), filtrirani i upareni do suhog. Sirovi produkt je pročišćen brzom kromatografijom (MeOH: CH2Cl2 (1:9 (volumski)). Skupljanje frakcija koje su sadržavale čisti produkt i uparavanje otapala je dalo čisti 1-[3-(1-propil-piperidin-4-il)-fenil]-etanon (35 mg). MS m/z (relativni intenzitet, 70 eV) 245 (M+, 4), 216 (bp), 100 (19), 70 (36), 57 (13).
Primjer 21: 1-Propil-4-(3-trifluormetilsulfonilfenil)-1,2,3,6-tetrahidropiridin
4-(3-Trifluormetilsulfonilfenil)-piridin (0,3 g) je otopljen u 1-jod-propanu (2 mL) i grijan do 100 ̊C kroz 2 h. Tada su hlapive tvari uparene i ostatak je otopljen u aps. EtOH (20 mL) i u obrocima je dodan NaBH4 (340 mg) kod -20 ̊C. Smjesa je tada ostavljena da postigne sobnu temperaturu i miješana je preko noći. Smjesi je dodana 10%-tna otopina Na2CO3 (20 mL). Vodeni dio je ekstrahiran s CH2Cl2 i skupljeni organski dijelovi su sušeni (MgSO4), filtrirani i upareni do suhog. Sirovi produkt je pročišćen brzom kromatografijom (MeOH: CH2Cl2 (1:9 (volumski)). Skupljanje frakcija koje su sadržavale čisti produkt i uparavanje otapala je dalo čisti 1-propil-4-(3-trifluormetilsulfonilfenil)-1,2,3,6-tetrahidropiridin (150 mg). MS m/z (relativni intenzitet, 70 eV) 333 (M+, 21), 305 (16), 304 (bp), 171 (14), 128 (14). Rf 0,55 (MeOH).
Primjer 22: 1-Propil-4-(3-trifluormetilsulfonilfenil)-piperidin
Počevši s 1-propil-4-(3-trifluormetilsulfonil-fenil)-1,2,3,6-tetrahidropiridinom, 1-propil-4-(3-trifluormetilsulfonilfenil)-piperidin je dobiven natrag postupkom opisanim u Pripravi 9. MS m/z (relativni intenzitet, 70 eV) 335 (M+, 3), 307 (17), 306 (bp), 173 (26), 70 (10).
Primjer 23: 1-Alil-4-(3-metansulfonil-fenil)-piperidin
Počevši s 4-(3-metansulfonil-fenil)-piperidinom i alilbromidom, naslovni spoj je dobiven postupkom opisanim u Primjeru 1. MS m/z (relativni intenzitet, 70 eV) 279 (M+, 74), 96 (bp), 82 (98), 68 (74), 55 (93). Rf = 0,42 (MeOH), 0,08 (EtOAc).
Primjer 24: 4-(3-Metansulfonil-fenil)-1-(tetrahidrofuran-2-ilmetil)-piperidin
Počevši s 4-(3-metansulfonil-fenil)-piperidinom i tetrahidrofurfuril kloridom, naslovni spoj je izoliran postupkom opisanim u Primjeru 1. MS m/z (relativni intenzitet, 70 eV) 323 (M+, 1), 252 (bp), 129 (9), 115 (6), 70 (17). Rf = 0,3 (MeOH), 0,03 (EtOAc).
Sinteze međuspojeva korištenih u gornjim Primjerima su opisane u pripravama ispod.
Priprava 1: 4-Hidroksi-4-(3-metilsulfanil-fenil)-piperidin-1-karboksilna kiselina tert-butil ester
1-Brom-3-metilsulfanil-benzen (5,0 g, 24,6 mmola) je otopljen u suhom THF (40 mL) i ohlađen je na -78 ̊C pod strujom argona (plin). Dokapan je n- BuLi (12,8 mL, 2,5 M u heksanu, 31,9 mmola) preko injekcije (syringe) i reakcijska smjesa je miješana dodatnih 30 min kod -78 ̊C i tada je temperatura povećana na 0 ̊C kroz 5 min i zatim opet smanjena na -78 ̊C. 1-tert-Butoksikarbonil-4-piperidon (5,4 g, 27,06 mmola) je otopljen u suhom THF (30 mL) i dodan kroz injekciju. Reakcijska smjesa je ostavljena da postigne sobnu temperaturu i tada je miješana kroz 1 sat i konačno prekinuta sa zasićenom otopinom amonijevog klorida (30 mL). Smjesa je ekstrahirana nekoliko puta s EtOAc i skupljeni organski dijelovi su sušeni (MgSO4), filtrirani i upareni do suhog. Uljasti ostatak je kromatografiran na stupcu silikagela uporabom CH2Cl2:MeOH (19:1 (volumno)) kao eluensom, dajući 4-hidroksi-4-(3-metilsulfanil-fenil)-piperidin-1-karboksilnu kiselinu tert-butilni ester (6 g, 76%). MS m/z (relativni intenzitet, 70 eV) 323,1 (M+, 6), 223,0 (11), 178,0 (7), 152 (3), 57,0 (bp), 56 (30).
Priprava 2: 1-Benzil-4-(3-metoksi-fenil)-piperidin-4-ol
Počevši s 3-bromanisolom (5 g) i 1-benzil-4-piperidonom (5,5 g), 4,58 g 1-benzil-4-(3-metoksi-fenil)-piperidin-ola je dobiveno postupkom opisanim u Pripravi 1. MS m/z (relativni intenzitet, 70 eV) 297 (M+, 8), 279 (13), 206 (28), 146 (17), 91 (bp).
Priprava 3: 1-Benzil-4-(3-trifluormetil-fenil)-piperidin-4-ol
Počevši s 3-trifluormetil-jodbenzenom (3 g) i 1-benzil-4-piperidonom (2,1 g). dobiveno je 1,75 g naslovnog spoja postupkom opisanim u pripravi 1. MS m/z (relativni intenzitet, 70 eV) 335 (M+, 29), 244 (22), 146 (19), 91 (bp), 56 (19).
Priprava 4: 4-(3-Metilsulfanil-fenil)-1,2,3,6-tetrahidro-piridin
4-Hidroksi-4-(3-metilsulfanil-fenil)-piperidin-1-karboksilna kiselina tert-butilni ester (3,97 g) je otopljen u CH2Cl2 (500 mL) i odjedanput je dodana trifluoroctena kiselina (80 mL). Smjesa je refluktirana kroz jedan sat i tada isprana s dva obroka 10%-tne Na2CO3, sušena (MgSO4), filtrirana i uparena do suhog. Iskorištenje 2,07 g. MS m/z (relativni intenzitet, 70 eV) 205 (M+, 73), 158 (44), 129 (95), 128 (80), 82 (bp).
Priprava 5: 1-Benzil-4-(3-metoksi-fenil)-1,2,3,6-tetrahidro-piridin
Počevši s 1-benzil-4-(3-metoksi-fenil)-piperidin-4-olom (4,5 g) i trifluoroctenom kiselinom (80 mL), dobiveno je 3,5 g 1-benzil-4-(3-metoksi-fenil)-1,2,3,6-tetrahidro-piridina postupkom opisanim u Pripravi 4. MS m/z (relativni intenzitet, 70 eV) 279 (M+, 35), 145 (13), 115 (15), 91 (bp), 65 (22).
Priprava 6: 1-Benzil-4-(3-trifluormetil-fenil)-1,2,3,6-tetrahidro-piridin
Počevši s 1-benzil-4-(3-trifluormetil-fenil)-piperidin-4-olom (1,74 g), dobiveno je 1,44 g naslovnog spoja prema postupku opisanom u pripravi 4 (čista CF3COOH). MS m/z (relativni intenzitet, 70 eV) 317 (M+, 71), 226 (13), 172 (15), 91 (bp), 65 (17).
Priprava 7: 4-(3-Metilsulfanil-fenil)-3,6-dihidro-2H-piridin-1-karboksilna kiselina metilni ester
4-(3-Metilsulfanil-fenil)-1,2,3,6-tetrahidro-piridin (2 g) i NEt3 (1 g) su otopljeni u CH2Cl2 (75 mL) i ohlađeni na 0°C. Dokapan je metil klorformat (0,96 g) otopljen u CH2Cl2 (20 mL) i reakcijska smjesa je tada ostavljena da postigne sobnu temperaturu. Nakon dodatna 2 h kod sobne temperature, reakcijska smjesa je oprana s 10%-tnom otopinom Na2CO3, sušena (MgSO4), filtrirana i koncentrirana uparavanjem. Uljasti ostatak je kromatografiran na stupcu silikagela korištenjem CH2Cl2:MeOH (19:1 (volumski)) kao eluensa, dajući 4-(3-metilsulfanil-fenil)-3,6-dihidro-2H-piridin-1-karboksilnu kiselinu metilni ester (1,4 g). MS m/z (relativni intenzitet, 70 eV) 263 (M+, 45), 248 (89), 129 (83), 128 (bp), 59 (96).
Priprava 8: 4-(3-Metansulfonil-fenil)-3,6-dihidro-2H-piridin-1-karboksilna kiselina metilni ester
4-(3-Metilsulfanil-fenil)-3,6-dihidro-2H-piridin-1-karboksilna kiselina metilni ester (1,4 g) je otopljena u CH2Cl2 (150 mL) i ohlađena na 0°C. m-Klorperoksibenzojeva kiselina (2,48 g) je dodana u obrocima i smjesa je miješana kod sobne temperature kroz tri sata. Nastala bistra otopina je isprana s 10%-tnom otopinom Na2CO3, sušena (MgSO4), filtrirana i koncentrirana uparavanjem, dajući uljasti ostatak (1,3 g). MS m/z (relativni intenzitet, 70 eV) 295 (M+, 19), 280 (56), 129 (70), 128 (89), 59 (bp).
Priprava 9: 4-(3-Metansulfonil-fenil)-piperidin-1-karboksilna kiselina metilni ester
4-(3-Metansulfonil-fenil)-3,6-dihidro-2H-piridin-1-karboksilna kiselina metilni ester (2,0 g) je otopljena u metanolu (40 mL). Dodani su koncentrirana klorovodična kiselina (2 mL) i Pd/C (500 mg). Nastala smjesa je hidrirana uz tlak plinovitog vodika (50 psi) kroz 8 sati i tada filtrirana kroz sloj celita. Otapalo je upareno u vakuumu i ostatak je pročišćen brzom kromatografijom (CH2Cl2:MeOH, 3:1 (volumski)). Iskorištenje 0,92 g MS m/z (relativni intenzitet, 70 eV) 297 (M+, 54), 282 (62), 238 (bp), 115 (92), 56 (93).
Priprava 10: 4-(3-Metoksi-fenil)-piperidin
Počevši s 1-benzil-4-(3-metoksi-fenil)-1,2,3,6-tetrahidro-piridinom (5,1 g) i 900 mg Pd/C, 1,7 g 4-(3-metoksi-fenil)-piperidina je dobiveno postupkom opisanim u Pripravi 9. Uljasti ostatak je pročišćen brzom kromatografijom (SiO2, CH2Cl2:MeOH, 3:1 (volumski) s 1%-tnim NEt3) da bi dao čisti naslovni spoj. MS m/z (relativni intenzitet, 70 eV) 191 (M+, 75), 160 (60), 83 (55), 57 (80), 56 (bp).
Priprava 11: 4-(3-Trifluormetil-fenil)-piperidin
Počevši s 1-benzil-4-(3-trifluormetil-fenil)-1,2,3,6-tetrahidro-piridina (1,44 g), dobiven je 1 g naslovnog spoja kao HCl sol postupkom opisanim u pripravi 9. T.t. 202°C (HCl); MS m/z (relativni intenzitet, 70 eV) 229 (M+, 44), 228 (33), 83 (12), 57 (54), 56 (bp).
Priprava 12: 4-(3-Metansulfonil-fenil)-piperidin
4-(3-Metansulfonil-fenil)-piperidin-1-karboksilna kiselina metilni ester (0,92 g) otopljen u etanolu (15 mL) i 8 M HCl (40 mL) su refluktirani kroz 12 sati. Smjesa je tada uparena u vakuumu do suhog. Iskorištenje 0,85 g MS m/z (relativni intenzitet, 70 eV) 239 (M+, 59), 238 (50), 69 (20), 57 (79), 56 (bp).
Priprava 13: 3-Piperidin-4-il-fenol
4-(3-Metoksi-fenil)-piperidin (1,7 g) je otopljen u 48%-tnoj HBr (60 mL) i miješan kod 120°C u atmosferi argona kroz 3 h. Suvišak HBr je tada uparen i dodan je aps. etanol i uparen. Ovaj postupak je ponovljen nekoliko puta da bi dao suhe kristale 3-piperidin-4-il-fenola x HBr (2,3 g). MS m/z (relativni intenzitet, 70 eV) 177 (M+, bp), 176 (23), 91 (14), 57 (44), 56 (60).
Priprava 14: 3-(1-Propil-piperidin-4-il)-fenol x HBr
Počevši s 3-piperidin-4-il-fenolom x HBr (300 mg) i n-propil jodidom (200 mg), dobiveno je 340 mg 3-(1-propil-piperidin-4-il)-fenola postupkom opisanim u Primjeru 1. HBr sol je pripravljena radi osiguranja naslovnog spoja. MS m/z (relativni intenzitet, 70 eV) 219 (M+, 21), 190 (bp), 119 (22), 91 (30), 70 (63); t.t. 181-184 °C (HBr).
Priprava 15: 3-(1-Etil-piperidin-4-il)fenol
Počevši s 3-piperidin-4-il-fenolom x HBr (200 mg) i etil jodidom (121 mg), dobiveno je 120 mg 3-(1-etil-piperidin-4-il)-fenola postupkom opisanim u Primjeru 1. MS m/z (relativni intenzitet, 70 eV) 205 (M+, 12), 190 (bp), 119 (36), 91 (22), 70 (87).
Priprava 16: 3-(1-Butil-piperidin-4-il)-fenol
Počevši s 3-piperidin-4-il-fenolom x HBr (200 mg) i n-butil kloridom (73 mg), dobiveno je 118 mg 3-(1-butil-piperidin-4-il)-fenola postupkom opisanim u Primjeru 1. MS m/z (relativni intenzitet, 70 eV) 233 (M+, 6), 190 (bp), 119 (42), 91 (26), 70 (45).
Priprava 17: 1-(3-Metansulfonil-fenil)-piperazin
Smjesa 1-brom-3-metansulfonil-benzena (0,8 g), piperazina (1 g), natrijevog tert-butoksida (0,5 g), BINAP (42 mg) i Pd2(dba)3 (38 mg) u toluenu (7 mL) je grijano pod argonom kod 80°C kroz 24 h. Nakon hlađenja na sobnu temperaturu, otapalo je upareno do suhog. Sirova tvar je pročišćena brzom kromatografijom na silikagelu koristeći EtOAc. Iskorištenje 0,48 g: MS m/z (relativni intenzitet, 70 eV) 240 (M+, 17), 199 (12), 198 (bp), 119 (9), 56 (7).
Priprava 18: 1-(3-Trifluormetansulfonil-fenil)-piperazin
Počevši s 3-brom-trifluormetansulfonil-benzenom i piperazinom, naslovni spoj je dobiven postupkom opisanim u Pripravi 17. MS m/z (relativni intenzitet, 70 eV) 294 (M+, 22), 252 (bp), 119 (32), 104 (10), 56 (15). (45).
Priprava 19: 1-(3-Piperazin-1-il-fenil)-etanon
Počevši s 3-brom-acetofenonom i piperazinom, naslovni spoj je dobiven postupkom opisanim u Pripravi 17. MS m/z (relativni intenzitet, 70 eV) 204 (M+, 5), 162 (35), 77 (30), 57 (35), 56 (bp).
Priprava 20: 3-(1-Propil-piperidin-4-il)-benzojeva kiselina metilni ester
Smjesa trifluor-metansulfonske kiseline 3-(1-propil-piperidin-4-il)-fenil estera (1,2 g), trietilamina (0,9 g), MeOH (5,4 mL), Pd(OAc)2 (25 mg) i 1,3-bis(di-fenil-fosfino)propana (45 mg) u 15 mL DMSO je miješana kod sobne temperature kroz 15 min. Kroz otopinu je puštana struja CO (plin) kroz 4-5 min, i tada je reakcijska posuda stavljena pod lagano pozitivan tlak CO (plin). Temperatura je porasla na 70°C. Nakon 6 h reakcija je ostavljena da se ohladi na sobnu temperaturu. Tada je dodana voda i vodena otopina je ekstrahirana s pet obroka etilnog acetata i skupljeni organski dijelovi su sušeni (MgSO4) i upareni. Ostatak je kromatografiran na stupcu silikagela uporabom MeOH:CH2Cl2 (1:9 (volumski)) kao eluensom. Frakcije koje su sadržavale čisti naslovni spoj su skupljene i otapalo je uklonjeno u vakuumu, dajući 650 mg naslovnog spoja. MS m/z (relativni intenzitet, 70 eV) 261 (M+, 5), 233 (16), 232 (bp), 161 (5), 70 (20).
Priprava 21: 3-(1-Propil-piperidin-4-il)-benzamid
Otopina 3-(1-propil-piperidin-4-il)-benzojeva kiselina metilni ester (0,6 g) i formamid (320 µL) u DMF (9 mL) su grijani na 100°C pod pokrovom argona. Dokapan je natrijev metoksid u metanolu (30%-tni, 770 µL) i nakon 1 h je GC analiza pokazala potpuni nestanak početne tvari i ukazivala na naslovni spoj kao jedini produkt. Nakon hlađenja je dodan CH2Cl2 i nastala otopina je filtrirana kroz sloj celita i uparena do suhog. Ostatak je kromatografiran na stupcu silikagela uporabom MeOH:CH2Cl2 (1:3 (volumski)) kao eluensom. Frakcije koje su sadržavala čisti naslovni spoj su skupljene i otapalo je uklonjeno u vakuumu, dajući 400 mg naslovnog spoja. T.t. 182 ̊C (oksalat) MS m/z (relativni intenzitet, 70 eV) 246 (M+, 4), 217 (bp), 131 (19), 100 (22), 70 (63).
Priprava 22: 4-(3-Trifluormetilsulfonil-fenil)-piridin
1-Brom-3-trifluormetilsulfonil benzen (580 mg) i 4-piridin-borna kiselina (275 mg) su otopljeni u toluenu (5 mL) i aps. EtOH (5 mL). Smjesi je tada dodan Na2CO3 (424 mg) i Pd(PPh3)4 (119 mg) u atmosferi argona. Nastala smjesa je grijana na 90 ̊C kroz 18 h. Tada je dodan CH2Cl2 i organski sloj je opran s vodom i sušen (MgSO4), filtriran i uparen do suhog. Ostatak je tada korišten bez bilo kakvog daljnjeg pročišćavanja. MS m/z (relativni intenzitet, 70 eV) 287 (M+, 33), 218 (22), 154 (bp), 127 (56), 69 (27).
Slijedeći testovi su korišteni za procjenu spojeva prema izumu.
In vivo test: Ponašanje
Za ispitivanje ponašanja su životinje smještene u odijeljene kutije za mjerenje pokretljivosti 50X50X50 cm opremljene s redom od 16x16 fotočelija (Digiscan activity monitor, RXYZM (16) TAO, Omnitech Eletronics, USA), povezan na Omnitech Digiscan analizator i Apple Macintosh računalo opremljeno s digitalnom interface pločom (NB DIO-24, National Instruments, USA). Podaci o ponašanju iz svake kutije za mjerenje pokretljivosti, predstavljajući položaj (središte gravitacije) životinje u svako doba, su snimljeni kod frekvencije uzorka od 25 Hz i skupljeni upotrebom LABView aplikacije. Podaci svakog snimanja su analizirani s obzirom na prevaljenu udaljenost i male kretnje, na primjer zaustavljanja u središtu arene za snimanje podataka, tijekom snimanja. Za određivanje zaustavljanja u središtu je izračunata brzina svake vremenske točke kao udaljenost pređena od prethodnog uzorka podijeljena s proteklim vremenom od prethodnog uzorka. Broj zaustavljanja je tada izračunat kao broj puta promjene brzine od ne nula vrijednosti do nule. Broj zaustavljanja u središtu arene za snimanje ponašanja je izračunat kao broj zaustavljanja koji se pojavljuje na položaju najmanje deset centimetara od rubova arene za snimanje. Za ispitivanje ponašanja nastanjenih štakora su životinje smještene u kutije za mjerenje pokretanja 30 minuta prije davanja spoja koji se ispituje. Svako snimanje ponašanja je trajalo 60 ili 30 minuta, počevši odmah nakon injektiranja spoja koji se ispituje. Slični postupci snimanja ponašanja su primjenjeni na nenastanjene štakore, nastanjene štakore i lijekom predtretirane štakore. Štakorima predtretiranim s d-amfetaminom su dane doze 1,5 mg/kg s.c. 5 min prije promatranja ponašanja u kutiji za mjerenje pokretljivosti. Štakori predtretirani s dizolcipinom (Mk-801) je dana doza 0,7 mg/kg i.p. 90 min prije promatranja ponašanja u kutiji za mjerenje pokretljivosti.
In vivo test: Neurokemija
Nakon promatranja aktivnosti ponašanja su štakori žrtvovani i njihovi mozgovi su brzo izvađeni i stavljeni u ohlađenu petrijevu zdjelicu. Limbični prednji mozak, striatum, prednji korteks i preostali polukružni dijelovi svakog štakora su razrezani i smrznuti. Svaki dio mozga je jedan za drugim analiziran s obzirom na svoj sadržaj monoamina i njihovih metabolita. Monoaminergični indikatori koji su analizirani su bili dopamin (DA), 3,4-dihidroksifeniloctena kiselina (DOPAC), homovanilinska kiselina (HVA), 3-metoksitiramin (3-MT), serotonin (5-HT), 5-hidroksiindoloctena kiselina (5-HIAA) i norandrenalin. Svi monoaminergični indikatori u izrezanim tkivima su analizirani uz pomoć HPLC s elektrokemijskom detekcijom kako je opisano od Svensson K. i ostalih, 1986., Naunyn-Schmiedeberg's Arch Pharmacol 334: 234-245 i u referencama koje su ondje citirane.
In vivo test: Farmakokinetika kod štakora
Radi određivanja oralne dostupnosti (F) i poluživota u plazmi (t1/2) ispitivanih spojeva prema izumu poduzeti su pokusi provedeni na štakorima. Na dan jedan štakorima je ugrađen jedan kateter u jugularnu venu i jedan kateter u karotidnu arteriju pod ketaminskom anestezijom. Na dan tri je injektiran spoj koji se ispituje bilo oralno bilo u kateter jugularne vene. Uzorci krvi su skupljani tijekom 8 sati iz arterijskog katetera. Uzorci krvi su heparinizirani i centrifugirani. Plazma je skupljana iz centrifugiranih uzoraka i smrznuta. Razine ispitivanog spoja su neposredno određene u svakom uzorku uz pomoć plinske kromatografije (Hewlett-Packard 5972MSD). Uzorci plazme uzeti od štakora Spraque-Dawley lanca, (0,5 mL) su razrjeđeni s vodom (0,5 mL) i dodano je 30 pmol (50 µL) ((-)-S-3-(3-etilsulfanilfenil)-N-n-propil-piperidina kao unutrašnjeg standarda. pH je podešen na 11,0 dodatkom 25 µL zasićenog Na2CO3. Nakon miješanja su uzorci ekstrahirani s 4 mL diklormetana potreskivanjem kroz 20 min. Organski sloj je, nakon centrifugiranja, prebačen u manju cijevčicu i uparen do suhog pod strujom dušika i neposredno ponovno otopljen u 40 µL toluena za GC-MS analizu. Pripravljena je standardna krivulja u rasponu 1-500 pmola dodavanjem odgovarajućih količina ispitivanog spoja u nadzorne uzorke plazme. GC je proveden na HP-Ultra 2 kapilarnoj koloni (12m x 0,2 mm ID) i injektirano je 2 µL na nerascijepan način. GC temperatura je držana kod 90 ̊C kroz 1 minutu nakon injektiranja i tada je povećavana 30 ̊C/min do konačne temperature od 290 ̊C. Svaki uzorak je propušten u duplikatu. Najniže detektirane koncentracije spoja koji se ispituje su nađene od 1 pmol/mL.
Claims (28)
1. 3-supstituirani 4-(fenil-N-alkil)-piperazinski spoj formule 1:
[image]
naznačen time, da
R1 je odabran iz skupine koja se sastoji od OSO2CF3, OSO2CH3, SO2R3, COCF3 COCH3 i COCH2CH3, pri čemu R3 je kao što je određen niže ;
R2 je odabran iz skupine koja se sastoji od C1 - C4 alkila, alila, CH2CH2OCH3, CH2CH2CH2F, CH2CF3, 3,3,3-triflorpropil, i 4,4,4-triflorbutil;
R3 je odabran iz skupine koja se sastoji od C1-C3 alkila, CF3 i N(CH3)2 ;
pod uvjetom da kada R1 je SO2R3 i R3 je C1-C3 alkil, tada R2 nije CH2CH2OCH3 ;
ili njihove farmaceutski prihvatljive soli .
2. Spoj prema zahtjevu 1, naznačen time, da R1 je odabran od skupine koja se sastoji od OSO2CF3, OSO2CH3, SO2CH3, SO2CF3 , COCH3 i SO2N(CH3)2 .
3. Spoj prema zahtjevu 1 ili zahtjevu 2, naznačen time, da R2 je odabran od skupine koja se sastoji od propila i etila.
4. Farmaceutski pripravak, naznačen time, da sadrži spoj prema jednom od zahtjeva 1-3 i jedan ili više farmaceutski prihvatljivih nosača ili diluenata.
5. Farmaceutski pripravak prema zahtjevu 4, naznačen time, da je za liječenje stanja odabranih od skupine koja se sastoji od jatrogenog i nejatrogenog Parkinsonizma, poremećaja kretanja, distonija, i Tourette-ove bolesti.
6. Farmaceutski pripravak prema zahtjevu 4, naznačen time, da je za liječenje Parkinsove bolesti.
7. Farmaceutski pripravak prema zahtjevu 4, naznačen time, da je za liječenje stanja odabranih od skupine koja se sastoji od jatrogenih i nejatrogenih psihoza i halucinacija.
8. Farmaceutski pripravak prema zahtjevu 4, naznačen time, da je za liječenje stanja odabranih od šizofrenih poremećaja i šizofrenije.
9. Farmaceutski pripravak prema zahtjevu 4, naznačen time, da je za liječenje stanja odabranih od skupine koja se sastoji od poremećaja raspoloženja i tjeskobe.
10. Farmaceutski pripravak prema zahtjevu 9, naznačen time, da rečeni poremećaji raspoloženja i tjeskobe su odabrani od manodepresivne bolesti, depresije i opsesivno-kompulsivne bolesti.
11. Farmaceutski pripravak prema zahtjevu 4, naznačen time, da je za liječenje stanja odabranih od skupune koja se sastoji poremećaja pomanjkanja pažnje, poremećaja autizma i kongnitivnih disfunkcija.
12. Farmaceutski pripravak prema zahtjevu 4, naznačen time, da je za liječenje Huntington-ove bolesti.
13. Farmaceutski pripravak prema zahtjevu 4, naznačen time, da je za liječenje poremećaja spavanja.
14. Farmaceutski pripravak prema zahtjevu 4, naznačen time, da je za liječenje poremećaja povezanih sa supstancom koja se odnosi na štetnost od alkohola i ovisnost o drogama.
15. Farmaceutski pripravak prema bilo kojem od zahtjeva 4-14, naznačen time, da je u obliku prikladnom za oralno uzimanje.
16. Farmaceutski pripravak prema zahtjevu 15, naznačen time, da je u obliku tableta.
17. Farmaceutski pripravak prema zahtjevu 15, naznačen time, da je u obliku kapsula.
18. Farmaceutski pripravak prema bilo kojem od zahtjeva 4-14, naznačen time, da je u obliku prikladnom za davanje injekcijom.
19. Upotreba spoja prema bilo kojem od zahtjeva 1-3, naznačena time, da je za proizvodnju farmaceutskog pripravka za liječenje stanja odabranih od skupine koja se sastoji od jatrogenog i nejatrogenog Parkinsonizma, poremećaja kretanja, distonija i Tourette-ove bolesti.
20. Upotreba spoja prema bilo kojem od zahtjeva 1-3, naznačena time, da je za proizvodnju farmaceutskog pripravka za liječenje Parkinson-ove bolesti.
21. Upotreba spoja prema bilo kojem od zahtjeva 1-3, naznačena time, da je za proizvodnju farmaceutskog pripravka za liječenje stanja odabranih od skupine koja se sastoji od jatrogenih i nejatrogenih psihoza i halucinacija.
22. Upotreba spoja prema bilo kojem od zahtjeva 1-3, naznačena time, da je za proizvodnju farmaceutskog pripravka za liječenje stanja koja su odabrana od shizofrenih poremećaja i shizofrenije.
23. Upotreba spoja prema bilo kojem od zahtjeva 1-3, naznačena time, da je za proizvodnju farmaceutskog pripravka za liječenje stanja koja su odabrana od skupine koja se sastoji od poremećaja raspoloženja i tjeskobe.
24. Upotreba prema zahtjevu 23, naznačena time, da rečeni poremećaji raspoloženja i tjeskobe su odabrani od manodepresivnih oboljenja, depresije i opsesivno-kompulsivne bolesti.
25. Upotreba spoja prema bilo kojem od zahtjeva 1-3, naznačena time, da je za proizvodnju farmaceutskog pripravka za liječenje stanja odabranih od skupine koja se sastoji od poremećaja nedostatka pažnje, autističnih poremećaja i kognitivnih disfunkcija.
26. Upotreba spoja prema bilo kojem od zahtjeva 1-3, naznačena time, da je za proizvodnju farmaceutskog pripravka za liječenje poremećaja spavanja.
27. Upotreba spoja prema bilo kojem od zahtjeva 1-3, naznačena time, da je za proizvodnju farmaceutskog pripravka za liječenje Huntington-ove bolesti.
28. Upotreba spoja prema bilo kojem od zahtjeva 1-3, naznačena time, da je za proizvodnju farmaceutskog pripravka za liječenje poremećaja povezanih sa supstancom koja se odnosi na štetnost od alkohola ili ovisnost o drogama.
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SE9904724A SE9904724D0 (sv) | 1999-12-22 | 1999-12-22 | New modulators of dopamine neurotransmission I |
PCT/SE2000/002674 WO2001046145A1 (en) | 1999-12-22 | 2000-12-22 | New modulators of dopamine neurotransmission |
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HR20050784A HRP20050784A2 (en) | 1999-12-22 | 2005-09-07 | New modulators of dopamine neurotransmission |
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HR20020540A HRP20020540B1 (hr) | 1999-12-22 | 2002-06-20 | Novi modulatori transmisije dopamina |
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EP (3) | EP1240142B1 (hr) |
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CN (2) | CN1255382C (hr) |
AT (3) | ATE254601T1 (hr) |
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BG (2) | BG110211A (hr) |
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CA (1) | CA2394602C (hr) |
CZ (1) | CZ303302B6 (hr) |
DE (3) | DE60006717T2 (hr) |
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HK (2) | HK1054229B (hr) |
HR (2) | HRP20020540B1 (hr) |
HU (1) | HU229605B1 (hr) |
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Families Citing this family (55)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE46117E1 (en) | 1999-12-22 | 2016-08-23 | Teva Pharmaceuticals International Gmbh | Modulators of dopamine neurotransmission |
SE9904723D0 (sv) | 1999-12-22 | 1999-12-22 | Carlsson A Research Ab | New modulators of dopamine neurotransmission II |
SE9904724D0 (sv) * | 1999-12-22 | 1999-12-22 | Carlsson A Research Ab | New modulators of dopamine neurotransmission I |
PE20020690A1 (es) * | 2000-11-03 | 2002-08-23 | Upjohn Co | Metodo y tratamiento y prevencion de los dolores de cabeza de migranas |
AU2002324846B2 (en) * | 2001-08-31 | 2007-05-10 | Childrens Hospital Medical Center | Phosphodiesterase activity and regulation of phosphodiesterase 1-B-mediated signaling in brain |
US7851629B2 (en) | 2004-06-08 | 2010-12-14 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission |
SE0401465D0 (sv) | 2004-06-08 | 2004-06-08 | Carlsson A Research Ab | New substituted piperdines as modulators of dopamine neurotransmission |
DE602005017784D1 (de) * | 2004-06-08 | 2009-12-31 | Nsab, Filial Af Neurosearch Sweden Ab | Neue disubstituierte phenylpiperidine als modulatoren der dopamin- und serotoninneurotransmission |
DK1773772T3 (da) | 2004-06-08 | 2010-09-13 | Nsab Af Neurosearch Sweden Ab | Nye disubstituerede phenylpiperidiner/piperaziner som modulatorer af dopaminneurotransmission |
AU2005254726A1 (en) * | 2004-06-18 | 2005-12-29 | Neurosearch A/S | Novel alkyl substituted piperazine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
NZ555095A (en) * | 2004-10-13 | 2010-07-30 | Nsab Af Neurosearch Sweden Ab | Process for the synthesis of 4-(3-sulfonylphenyl)-piperidines |
EP1802573B1 (en) * | 2004-10-13 | 2016-09-28 | Teva Pharmaceuticals International GmbH | Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-n-propyl-piperidine |
DE602006007550D1 (de) * | 2005-02-10 | 2009-08-13 | Neurosearch As | Alkylsubstituierte homopiperazinderivate und deren verwendung als monoamin neurotransmitter wiederaufnahmeinhibitoren |
SE529246C2 (sv) * | 2005-10-13 | 2007-06-12 | Neurosearch Sweden Ab | Nya disubstituerade fenyl-piperidiner som modulatorer för dopaminneurotransmission |
WO2007065655A1 (en) | 2005-12-07 | 2007-06-14 | Neurosearch Sweden Ab | Disubstituted phenylpiperidines as modulators of cortical catecholaminergic neurotransmission |
CN101400676A (zh) * | 2006-03-10 | 2009-04-01 | 纽约州州立大学研究基金会 | 具有中枢神经系统活性的托烷类前药 |
CA2667510A1 (en) * | 2006-10-27 | 2008-06-12 | Janssen Pharmaceutica N.V. | Methods for treating disruptive behavior disorders |
AU2007346591A1 (en) * | 2007-02-07 | 2008-08-14 | Gosforth Centre (Holdings) Pty Ltd | Treatment of ADHD |
EP2146961B1 (en) * | 2007-04-12 | 2014-01-29 | IVAX International GmbH | N-oxide and/or di-n-oxide derivatives of dopamine receptor stabilizers/modulators displaying improved cardiovascular side-effects profiles |
CA2689692A1 (en) | 2007-06-05 | 2008-12-11 | Clas Sonesson | New disubstituted phenylpyrrolidines as modulators of cortical catecholaminergic neurotransmission |
EP2170327B1 (en) * | 2007-06-18 | 2014-10-22 | A.Carlsson Research AB | Use of dopamine stabilizers |
KR20100135325A (ko) * | 2008-04-29 | 2010-12-24 | 엔에스아베 필리알 아프 뉴로서치 스웨덴 아베 스베리게 | 도파민 신경전달의 조절제 |
US20110105462A1 (en) * | 2008-04-29 | 2011-05-05 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Modulators of dopamine neurotransmission |
AU2009242095A1 (en) * | 2008-04-29 | 2009-11-05 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Modulators of dopamine neurotransmission |
SG10201507362TA (en) | 2009-08-05 | 2015-10-29 | Intra Cellular Therapies Inc | Novel Regulatory Proteins And Inhibitors |
JP6173693B2 (ja) * | 2010-02-24 | 2017-08-02 | リサーチ・トライアングル・インスティチュート | アリールピペラジンオピオイド受容体アンタゴニスト |
WO2011107583A1 (en) | 2010-03-04 | 2011-09-09 | Nsab, Filial Af Neurosearch Sweden Ab, Sverige | Substituted 4-phenyl-n-alkyl-piperidines for preventing onset or slowing progression of neurodegenerative disorders |
EP2611759A1 (en) * | 2010-09-03 | 2013-07-10 | Ivax International Gmbh | Deuterated analogs of pridopidine useful as dopaminergic stabilizers |
EP2618826B1 (en) * | 2010-09-20 | 2016-04-13 | A.Carlsson Research AB | Phenylpiperidine compounds for the treatment of dementia |
EA023462B1 (ru) | 2011-09-07 | 2016-06-30 | Тева Фармасьютикалз Интернэшнл Гмбх | Полиморфная форма гидрохлорида придопидина |
US9012476B2 (en) | 2011-12-08 | 2015-04-21 | IVAX International GmbH | Hydrobromide salt of pridopidine |
EA027748B1 (ru) | 2012-04-04 | 2017-08-31 | Тева Фармасьютикалз Интернэшнл Гмбх | Применение придопидина в комбинации с тетрабеназином для лечения двигательных нарушений и ожирения |
CA2879020C (en) | 2012-07-12 | 2021-02-09 | Psyadon Pharmaceuticals, Inc. | Fused benzazepines for treatment of tourette's syndrome |
US20150216850A1 (en) * | 2012-09-27 | 2015-08-06 | Michael Hayden | Combination of rasagiline and pridopidine for treating neurodegenerative disorders, in particular huntington's disease |
US11090297B2 (en) | 2013-06-21 | 2021-08-17 | Prilenia Neurotherapeutics Ltd. | Pridopidine for treating huntington's disease |
AU2014281414A1 (en) | 2013-06-21 | 2016-01-21 | Teva Pharmaceuticals International Gmbh | Use of high dose pridopidine for treating Huntington's disease |
DK3057595T3 (da) * | 2013-10-18 | 2020-08-10 | Emalex Biosciences Inc | Smeltebenzazepiner til behandling af stammen |
ES2911800T3 (es) | 2014-01-22 | 2022-05-20 | Prilenia Neurotherapeutics Ltd | Formulaciones de liberación modificada de pridopidina |
TW201613859A (en) | 2014-06-30 | 2016-04-16 | Teva Pharma | Analogs of PRIDOPIDINE, their preparation and use |
JP2018505147A (ja) | 2014-12-22 | 2018-02-22 | テバ・ファーマシューティカルズ・インターナショナル・ゲーエムベーハー | プリドピジンのl−酒石酸塩 |
US11471449B2 (en) | 2015-02-25 | 2022-10-18 | Prilenia Neurotherapeutics Ltd. | Use of pridopidine to improve cognitive function and for treating Alzheimer's disease |
US10603311B2 (en) | 2015-02-25 | 2020-03-31 | Prilenia Neurotherapeutics Ltd. | Use of pridopidine to improve cognitive function and for treating Alzheimer's disease |
EP3294337A1 (en) | 2015-05-13 | 2018-03-21 | A.Carlsson Research AB | Treatment of debilitating fatigue |
AR105434A1 (es) * | 2015-07-22 | 2017-10-04 | Teva Pharmaceuticals Int Gmbh | Proceso para preparar pridopidina |
US11738012B2 (en) | 2016-02-24 | 2023-08-29 | Prilenia Neurotherapeutics Ltd. | Treatment of neurodegenerative eye disease using pridopidine |
CA3035099C (en) * | 2016-08-24 | 2023-01-17 | Prilenia Therapeutics Development Ltd. | Use of pridopidine for treating dystonias |
CA3035092C (en) | 2016-08-24 | 2022-05-31 | Prilenia Therapeutics Development Ltd. | Use of pridopidine for treating functional decline |
ES2909557T3 (es) | 2016-09-16 | 2022-05-09 | Prilenia Neurotherapeutics Ltd | Utilización de la pridopidina para el tratamiento del síndrome de Rett |
CN110505902B (zh) | 2017-01-20 | 2022-11-11 | 普瑞尼亚神经治疗有限公司 | 普利多匹定用于治疗脆性x综合征的应用 |
EP3357909A1 (en) | 2017-02-02 | 2018-08-08 | Sandoz AG | Crystalline 4-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine |
MX2020001836A (es) | 2017-08-14 | 2020-08-10 | Prilenia Neurotherapeutics Ltd | Metodo para tratar esclerosis lateral amiotrofica con pridopidina. |
EP3675830A1 (en) | 2017-08-30 | 2020-07-08 | Prilenia Neurotherapeutics Ltd. | High concentration dosage forms of pridopidine |
MX2020002645A (es) | 2017-09-08 | 2021-06-10 | Prilenia Neurotherapeutics Ltd | Pridopidina para el tratamiento de las discinesias inducidas por fármacos. |
WO2023049480A1 (en) * | 2021-09-25 | 2023-03-30 | Alexander Shulgin Research Institute | Substituted phenylalkylamines |
WO2023214412A1 (en) * | 2022-05-03 | 2023-11-09 | Prilenia Neurotherapeutics Ltd. | Processes and intermediates for the preparation of pridopidine |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB850662A (en) | 1956-10-22 | 1960-10-05 | Parke Davis & Co | Substituted piperazines and processes for their production |
BE662455A (hr) * | 1964-04-14 | |||
FR1459013A (fr) | 1964-08-05 | 1966-04-29 | Allen & Hanburys Ltd | Procédé de préparation de dérivés de la 4-phényl-pipéridine |
GB1060160A (en) * | 1964-08-05 | 1967-03-01 | Allen & Hanburys Ltd | 4-phenylpiperidine derivatives |
US3539573A (en) | 1967-03-22 | 1970-11-10 | Jean Schmutz | 11-basic substituted dibenzodiazepines and dibenzothiazepines |
ZA7546B (en) * | 1974-01-21 | 1976-08-25 | Parke Davis & Co | New antibacterial amide compounds and methods for their production |
GB1560271A (en) * | 1977-01-14 | 1980-02-06 | Joullie International Sa | Therapeutically useful m-trifluoromethylphenylpiperazine derivatives |
US4202898A (en) * | 1978-06-05 | 1980-05-13 | Synthelabo | Method of treating anxiety and depression |
FR2429212A1 (fr) * | 1978-06-20 | 1980-01-18 | Synthelabo | Derives de phenylpiperazine et leur application en therapeutique |
FR2459797A2 (fr) * | 1978-08-01 | 1981-01-16 | Synthelabo | Derives de phenyl-1 piperazine et leur application en therapeutique |
US4267328A (en) * | 1978-08-01 | 1981-05-12 | Synthelabo | 1-Phenylpiperazines |
US4333942A (en) | 1979-08-03 | 1982-06-08 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Anti-depressant and analgesic 4-phenoxypiperidines |
SE446335B (sv) * | 1982-03-30 | 1986-09-01 | Astra Laekemedel Ab | Ren enantiomer av en metasubstituerad 3-fenyl-1-propylpiperidin |
US4518712A (en) | 1980-06-30 | 1985-05-21 | Taiho Pharmaceutical Company Limited | Piperazine derivative and analgesic composition containing the same |
GB2083476B (en) | 1980-09-12 | 1984-02-08 | Wyeth John & Brother Ltd | Heterocyclic compounds |
FR2501506A1 (fr) * | 1981-03-11 | 1982-09-17 | Sanofi Sa | Compositions pharmaceutiques a action anorexigene contenant des derives de la tetrahydropyridine |
US4415736A (en) | 1981-12-28 | 1983-11-15 | E. I. Du Pont De Nemours & Co. | Certain tetrahydropyridine intermediates |
EP0094159B1 (en) | 1982-05-10 | 1990-03-14 | Takeda Chemical Industries, Ltd. | Dihydropyridine derivatives, their production and use |
US4504660A (en) | 1982-07-06 | 1985-03-12 | American Home Products Corporation | Process for the production of 2,6-diaminobenzonitrile derivatives |
HU198454B (en) | 1987-12-14 | 1989-10-30 | Richter Gedeon Vegyeszet | Process for production of new derivatives of tetrahydrospiridin and medical compositions containing these compounds |
FR2639226B1 (fr) * | 1988-11-18 | 1993-11-05 | Sanofi | Utilisation de trifluoromethylphenyltetrahydropyridines pour la preparation de medicaments destines a combattre les troubles anxio-depressifs |
AU7162791A (en) * | 1989-12-27 | 1991-07-24 | Miroslav Radman | Novel system for isolating and producing new genes, gene products and dna sequences |
CA2071897A1 (en) * | 1989-12-28 | 1991-06-29 | Richard A. Glennon | Sigma receptor ligands and the use thereof |
ATE201669T1 (de) | 1991-04-17 | 2001-06-15 | Upjohn Co | Substituierte (s)-3-phenylpiperidin derivate, deren herstellung und deren verwendung als dopamin autorezeptor antagonisten |
EP0591426A4 (en) * | 1991-06-27 | 1996-08-21 | Univ Virginia Commonwealth | Sigma receptor ligands and the use thereof |
IE914218A1 (en) | 1991-09-11 | 1993-03-24 | Mcneilab Inc | Novel 4-arylpiperazines and 4-arylpiperidines |
GB9119920D0 (en) | 1991-09-18 | 1991-10-30 | Glaxo Group Ltd | Chemical compounds |
ATE204262T1 (de) | 1991-09-18 | 2001-09-15 | Glaxo Group Ltd | Benzanilidderivate als 5-ht1d-antagonisten |
GB9119932D0 (en) | 1991-09-18 | 1991-10-30 | Glaxo Group Ltd | Chemical compounds |
CN1036395C (zh) * | 1992-03-19 | 1997-11-12 | 约翰韦恩兄弟有限公司 | 哌嗪衍生物的制备方法 |
US5502050A (en) | 1993-11-29 | 1996-03-26 | Cornell Research Foundation, Inc. | Blocking utilization of tetrahydrobiopterin to block induction of nitric oxide synthesis |
CA2144669A1 (en) | 1994-03-29 | 1995-09-30 | Kozo Akasaka | Biphenyl derivatives |
AU6470096A (en) | 1995-07-19 | 1997-02-18 | Yoshitomi Pharmaceutical Industries, Ltd. | Fused triazole compounds |
US5892041A (en) | 1996-08-12 | 1999-04-06 | Neurogen Corporation | Fused indolecarboxamides: dopamine receptor subtype specific ligands |
DE19637237A1 (de) * | 1996-09-13 | 1998-03-19 | Merck Patent Gmbh | Piperazin-Derivate |
CA2288172A1 (en) * | 1997-04-18 | 1998-10-29 | Smithkline Beecham P.L.C. | A bicyclic aryl or a bicyclic heterocyclic ring containing compounds having a combined 5ht1a, 5ht1b and 5ht1d receptor antagonistic activity |
SE9702799D0 (sv) * | 1997-07-25 | 1997-07-25 | Astra Ab | New compounds |
US6303627B1 (en) * | 1998-06-19 | 2001-10-16 | Eli Lilly And Company | Inhibitors of serotonin reuptake |
JP5035813B2 (ja) * | 1998-07-10 | 2012-09-26 | マサチューセッツ インスティテュート オブ テクノロジー | 金属用のリガンドおよびそれらに基づいて改善された金属触媒法 |
US6232326B1 (en) * | 1998-07-14 | 2001-05-15 | Jodi A. Nelson | Treatment for schizophrenia and other dopamine system dysfunctions |
RU2243226C2 (ru) | 1999-06-22 | 2004-12-27 | НьюроСёрч А/С | Новые производные бензимидазола и содержащие эти соединения фармацевтические композиции |
SE9904723D0 (sv) | 1999-12-22 | 1999-12-22 | Carlsson A Research Ab | New modulators of dopamine neurotransmission II |
SE9904724D0 (sv) * | 1999-12-22 | 1999-12-22 | Carlsson A Research Ab | New modulators of dopamine neurotransmission I |
AU2001280599A1 (en) | 2000-07-15 | 2002-01-30 | Smith Kline Beecham Corporation | Compounds and methods |
ES2247298T3 (es) | 2001-01-23 | 2006-03-01 | Eli Lilly And Company | Derivados de piperazina y piperidina como agonistas del receptor de melanocortina. |
US20050004164A1 (en) | 2003-04-30 | 2005-01-06 | Caggiano Thomas J. | 2-Cyanopropanoic acid amide and ester derivatives and methods of their use |
US7160888B2 (en) | 2003-08-22 | 2007-01-09 | Warner Lambert Company Llc | [1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia |
SE0401465D0 (sv) | 2004-06-08 | 2004-06-08 | Carlsson A Research Ab | New substituted piperdines as modulators of dopamine neurotransmission |
DK1773772T3 (da) * | 2004-06-08 | 2010-09-13 | Nsab Af Neurosearch Sweden Ab | Nye disubstituerede phenylpiperidiner/piperaziner som modulatorer af dopaminneurotransmission |
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