HRP20051024A2 - Farmaceutski aktivni morfolinol - Google Patents
Farmaceutski aktivni morfolinol Download PDFInfo
- Publication number
- HRP20051024A2 HRP20051024A2 HR20051024A HRP20051024A HRP20051024A2 HR P20051024 A2 HRP20051024 A2 HR P20051024A2 HR 20051024 A HR20051024 A HR 20051024A HR P20051024 A HRP20051024 A HR P20051024A HR P20051024 A2 HRP20051024 A2 HR P20051024A2
- Authority
- HR
- Croatia
- Prior art keywords
- compound
- morpholinol
- formula
- chlorophenyl
- trimethyl
- Prior art date
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- OURXRFYZEOUCRM-UHFFFAOYSA-N 4-hydroxymorpholine Chemical compound ON1CCOCC1 OURXRFYZEOUCRM-UHFFFAOYSA-N 0.000 title description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000012453 solvate Substances 0.000 claims abstract description 11
- RCOBKSKAZMVBHT-TVQRCGJNSA-N radafaxine Chemical compound C[C@@H]1NC(C)(C)CO[C@@]1(O)C1=CC=CC(Cl)=C1 RCOBKSKAZMVBHT-TVQRCGJNSA-N 0.000 claims abstract description 5
- 230000003287 optical effect Effects 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- ORXTVTDGPVINDN-BTJVGWIPSA-N (2s,3s)-2-(3-chlorophenyl)-3,5,5-trimethylmorpholin-2-ol;hydrochloride Chemical group Cl.C[C@@H]1NC(C)(C)CO[C@@]1(O)C1=CC=CC(Cl)=C1 ORXTVTDGPVINDN-BTJVGWIPSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 10
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 abstract description 9
- 229960002715 nicotine Drugs 0.000 abstract description 9
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 abstract description 9
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
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- OFCNTYBPPAQCRE-UHFFFAOYSA-N 3-(2-aminoethyl)-3h-indol-5-ol Chemical compound C1=C(O)C=C2C(CCN)C=NC2=C1 OFCNTYBPPAQCRE-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
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Abstract
Otkriven je spoj (+)-(2S,3S)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol i njegove farmaceutski prihvatljive soli i solvati, farmaceutski pripravci koji ih sadrže; također je otkriven postupak za liječenje depresije, hiperaktivnog poremećaja nedostatka pažnje (ADHD), pretilosti, migrene, boli, seksualne disfunkcije, Parkinsonove bolesti, Alzheimerove bolesti, ovisnosti o kokainu ili o proizvodima koji sadrže nikotin (naročito duhan) koji upotrebljava taj spoj, soli, solvate ili pripravke.
Description
Ovaj izum se odnosi na optički čist morfolinol, njegove soli i solvate, farmaceutske pripravke koji ih sadrže i postupke za njihovo dobivanje i upotrebu.
Pozadina izuma
Bupropion hidroklorid, (±)-1-(3-klorfenil)-2-[(1,1-dimetiletil)-amino]-1-propanon hidroklorid, je aktivni sastojak lijeka Wellbutrin®, koji je na tržištu u Sjedinjenim Državama za liječenje depresije. To je također aktivni sastojak lijeka Zyban®, koji je na tržištu u Sjedinjenim Državama kao pomoć pri prestanku pušenja. Bupropion je relativno slab inhibitor preuzimanja noradrenalina (NA), serotonina i dopamina (DA) i neuronima, i ne inhibira monoamin oksidaze. Iako je mehanizam djelovanja bupropiona, kao i ostalih antidepresiva, nepoznat, pretpostavlja se da je ovo djelovanje posredovano noradrenergičnim i/ili dopaminergičnim mehanizmima. Dostupni dokazi ukazuju da je Wellbutrin® selektivni inhibitor noradrenalina (NA), u dozama za koje je predviđeno da imaju antidepresivnu aktivnost na životinjskim modelima. Vidi Ascher, J.A., i sur., Bupropion: A Review of its Mechanism of Antidepressant Activity. Journal of Clinical Psychiatry, 56:p. 396-401, 1995.
[image]
Bupropion se znatno metabolizira u čovjeku kao i u laboratorijskim životinjama. Metaboliti u urinu i plazmi uključuju produkte biotransformacije formirane hidroksilacijom terc-butil skupine i/ili redukcijom karbonilne skupine bupropiona. Identificirana su četiri osnovna metabolita. Oni su eritro- i treo-amino alkoholi bupropiona, eritro-amino diol bupropiona, i morfolinol metabolit. Ti metaboliti bupropiona su farmakološki aktivni, ali njihova jakost i toksičnost u odnosu na bupropion nisu potpuno karakterizirane. Zbog toga što su koncentracije metabolita u plazmi više od koncentracija bupropiona, oni mogu biti od kliničke važnosti.
Vjeruje se da morfolinol metabolit, (±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol hidroklorid, nastaje hidroksilacijom terc-butil skupine bupropiona.
[image]
U Biomed. Chromatogr. (1997), 11(3), 174-179 (Suckow, R.F. i sur.) je otkriveno odvajanje i kvantifikacija pojedinačnih enantiomera (±)-(2RS,3RS) racemičnog morfolinol metabolita i naznačeno bez naznake djelovanja, kao i činjenica da uzorci plazme sadržavaju (-)-enantiomer do oko 96% ukupne količine ovog metabolita. Međutim, nema informacija što se tiče farmakoloških karakteristika svakog enantiomera i njegove kliničke važnosti koja proizlazi iz toga.
Kratak opis izuma
Sada je iznenađujuće otkriveno da, usprkos tome što (-) oblik morfolinol metabolita znatno dominira u uzorcima ljudske plazme, (+) enantiomer, (+)-(2S,3S)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol je taj u kojem se nalazi aktivnost.
Prema tome, ovaj izum pruža, u jednom aspektu, farmaceutski prihvatljive soli i solvate spoja formule (I), (+)-(2S,3S)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinola.
[image]
Te farmaceutski prihvatljive soli uključuju, ali nisu ograničene na, one dobivene od sljedećih kiselina: kloridne, bromidne, sulfatne, nitratne, fosfatne, salicilne, p-toluensulfonske, vinske, limunske, metansulfonske, maleinske, mravlje, malonske, sukcinske, izetionske, laktobionske, naftalen-2-sulfonske, sulfaminske, etansulfonske i benzensulfonske. Naročito poželjna je hidrokloridna sol spoja formule (I).
Drugi aspekt izuma su farmaceutski pripravci koji sadržavaju spoj formule (I) ili njegove farmaceutski prihvatljive soli i solvate, zajedno s jednim ili više farmaceutski prihvatljivih nosača, razrjeđivača ili ekscipijenata.
Daljnji aspekt izuma je upotreba spoja formule (I) ili njegovih farmaceutski prihvatljivih soli ili solvata u terapiji.
Još jedan aspekt izuma pruža postupke za liječenje depresije, hiperaktivnog poremećaja nedostatka pažnje (ADHD), pretilosti, migrene, boli, seksualne disfunkcije, Parkinsonove bolesti, Alzheimerove bolesti, ili ovisnosti o kokainu ili proizvodima koji sadrže nikotin (naročito duhan) kod ljudskog ili životinjskog subjekta, koji sadrži primjenu spomenutom subjektu djelotvorne količine spoja formule (I) ili njegovih farmaceutski prihvatljivih soli ili solvata ili njihovih farmaceutskih pripravaka.
Još jedan aspekt ovog izuma je upotreba spoja formule (I) ili njegovih farmaceutski prihvatljivih soli ili solvata ili njihovih farmaceutskih pripravaka, za dobivanje lijeka za liječenje depresije, hiperaktivnog poremećaja nedostatka pažnje (ADHD), pretilosti, migrene, boli, seksualne disfunkcije, Parkinsonove bolesti, Alzheimerove bolesti, ili ovisnosti o kokainu ili proizvodima koji sadrže nikotin (naročito duhan).
Opis slika
Slika 1. Djelovanje spojeva u koncentraciji od 25 mg/kg (ip) na TBZ-induciranu depresiju
Slika 2. Reakcija na dozu spoja formule I protiv TBZ-inducirane depresije (spojevi primijenjeni 30 minuta prije TBZ, muški, CD-1 miševi, i.p., n=6)
Slika 3. Reakcija na dozu spoja formule II protiv TBZ-inducirane depresije (spojevi primijenjeni 30 minuta prije TBZ, muški, CD-1 miševi, i.p., n=6)
Detaljan opis izuma
Spoj formule (I) ili njegove farmaceutski prihvatljive soli i solvati se mogu pripraviti tako da se najprije sintetizira racemat morfolinol metabolita bupropiona i nakon toga se odvoje (+) i (-) enantiomeri racemata pomoću HPLC.
Racemat morfolinol metabolita bupropion hidroklorida ((±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol hidroklorid) se može sintetizirati sljedećim postupkom. 3’-klorpropiofenonu (10,0 g, 0,06 mol) u dioksanu (50 mL) se doda otopina dioksan dibromida (14,9 g, 0,06 mol) u dioksanu (50 mL). Reakcijska smjesa se miješa 2 h na sobnoj temperaturi i izlije u smjesu leda i vode (500 mL). Smjesa se ekstrahira nekoliko puta sa metilen kloridom. Sjedinjeni ekstrakt se osuši (Na2SO4) i koncentrira u vakuumu da se dobije 14,8 g (85%) 2-brom-3’-klorpropiofenona kao blijedo žutog ulja. To se upotrijebi bez daljnjeg pročišćavanja.
NMR (300 MHz, CDCl3); δ 7,99 (m, 1H), 7,90 (d, 1H), 7,57 (d, 1H), 7,44 (t, 1H), 5,22 (q, 1H), 1,91 (t, 3H).
Otopini 2-brom-3’-klorpropiofenona (19,3 g, 0,08 mol) u MeOH (100 mL) se doda kap po kap otopina 2-amino-2-metil-1-propanola (27,8 g, 0,31 mol) u metanolu (200 mL) na sobnoj temperaturi. Smjesa se miješa 18 h i koncentrira u vakuumu. Ostatak se razdijeli između vode i dietil etera. Sjedinjena organska faza se ekstrahira sa 10%-tnim vodenim klorovodikom. Sjedinjeni ekstrakt u vodenoj kiselini se ohladi u ledenoj kupelji i zaluži sa 40%-tnim natrij hidroksidom. Smjesa se ekstrahira sa dietil eterom, sjedinjeni ekstrakt u dietil eteru se ispere sa vodom i zasićenom otopinom natrij klorida, osuši (K2CO3) i koncentrira u vakuumu da se dobije 15,0 g (75%) (±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol kao sivobijela krutina.
(±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol se može prevesti u (±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol hidroklorid sljedećim postupkom. Uzorak od 6,0 g se otopi u dietil eteru, ohladi u ledenoj kupelji i doda se eterski klorovodik dok smjesa ne bude kisela. Dobivena krutina se filtrira i prekristalizira iz smjesa etanola/dietil etera/eterskog klorovodika da se dobije 4,93 g (±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol hidroklorida kao bijele krutine: talište 202-203°C.
NMR (80 MHz, DMSO-d6); δ 10,9 (br, 1H), 8,85 (br, 1H), 7,60-7,41 (m, 5H), 4,04 (d, 1H), 3,50 (d, 1H), 3,37 (br s, 1H), 1,58 (s, 3H), 1,34 (s, 3H), 1,03 (d, 3H).
Anal. izračunato za C13H19Cl2NO2: C, 53,43; H, 6,55; N, 4,79. Ustanovljeno: C, 53,54; H, 6,58; N, 4,75.
(±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol hidroklorid se može ponovno prevesti u svoj oblik slobodne baze sljedećim postupkom. Uzorak od 3,0 g (±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol hirdoklorida se otopi u vodi (100 mL) i doda se dietil eter (200 mL). Smjesa se ohladi u ledenoj kupelji i pH se podesi na >10 pomoću 1,0N vodenog natrij hidroksida. Nakon miješanja 30 min, faze se odvoje i vodena faza se ekstrahira sa dietil eterom. Sjedinjeni ekstrakt u dietil eteru se osuši (Na2SO4) i koncentrira u vakuumu, da se dobije 2,6 g (±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinola kao bijele krutine. To se upotrijebi bez daljnjeg pročišćavanja za kiralnu kromatografiju opisanu niže.
(+) i (-) enantiomeri (±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinola se mogu odvojiti sljedećim postupkom. (±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol (2,54 g) se otopi u 250 mL 2:8 izopropil alkohol:heksan (oba HPLC-kakvoće). Daicel Chiralcel OD stupac (2 × 25 cm) se ekvilibrira jedan sat uz 8 mL/min u otapalu za razvijanje, 1:9:0,2 izopropanol:heksan:dietilamin. Otopina (±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinola se injicira u alikvotima od 1 mL upotrebom automatiziranog Waters Prep LC 2000, pomoću Waters 510 EF pumpe za injekcije. Svaka dionica je trajala 15 minuta, uz gore navedene uvjete. Odvojeni optički izomeri su sakupljeni pomoću sakupljača frakcija (Waters) uz prag od 2% iznad osnovne vrijednosti, bazirano na 2 jedinice apsorbancije potpunog mjerila pri 240 nm (Waters 490E UV detektor). Svaki optički izomer je uparen na rotacijskom uparivaču pri 40°C i uz aspiracijski vakuum. Nakon sušenja 6 sati pod visokim vakuumom na sobnoj temperaturi, optički izomer 1 je imao masu 1,25 g, a optički izomer 2 je imao masu 1,26 g.
Enantiomerna čistoća svakog izomera je ispitana pomoću analitičke kiralne HPLC na Waters 860 HPLC sa 996 Photodiode Array detektorom, upotrebom Daicel Chiralcel OD-H stupca (4,6 × 250 mm), razvijanjem sa 1:9:0,2 izopropil alkohol:heksan:dietilamin uz 1 mL/min. Optički izomer je bio 100% čist (R.T. 6,117 min). Optički izomer 2 je bio 99,19% čist (R.T. 6,800 min), sadržavao je 0,91% optičkog izomera 1 (R.T. 6,133 min).
Hidrokloridne soli odvojenih enantiomera su dobivene sljedećim postupcima. 1,25 g (0,005 mol) optičkog izomera 1 (vrijeme zadržavanja 6,117 min) ((-)-(2R,3R)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol) se otopi u dietil eteru. Otopina se filtrira i filtrat se ohladi u ledenoj kupelji uz dodavanje eterskog klorovodika dok otopina ne bude kisela. Nakon stajanja na sobnoj temperaturi 24 h, dobivena otopina se filtrira, ispere sa dietil eterom i suši u vakuumskom sušioniku pri 60°C 18 h, da nastane 1,32 g (90%) (-)-(2R,3R)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol hidroklorida kao bijele krutine: talište 208-209°C.
NMR (300 MHz, DMSO-d6); δ 9,72 (br, 1H), 8,76 (br, 1H), 7,54-7,41 (m, 5H), 3,98 (d, 1H), 3,52 (d, 1H), 3,37 (br s, 1H), 1,53 (s, 3H), 1,29 (s, 3H), 0,97 (d, 3H).
Anal. izračunato za C13H19Cl2NO2: C, 53,43; H, 6,55; N, 4,79. Ustanovljeno: C, 53,35; H, 6,57; N, 4,71.
[α]D20°C = -33,2° (0,67, 95% EtOH)
1,26 g (0,005 mol) optičkog izomera 2 (vrijeme zadržavanja 6,800 min) ((+)-(2S,3S)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol) se otopi u dietil eteru. Otopina se filtrira i filtrat se ohladi u ledenoj kupelji uz dodavanje eterskog klorovodika dok otopina ne bude kisela. Nakon stajanja na sobnoj temperaturi 24 h, dobivena otopina se filtrira, ispere sa dietil eterom i suši u vakuumskom sušioniku pri 60°C 18 h, da nastane 1,36 g (93%) (+)-(2S,3S)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol hidroklorida kao bijele krutine: talište 208-209°C.
NMR (300 MHz, DMSO-d6); δ 9,87 (br, 1H), 8,76 (br, 1H), 7,54-7,41 (m, 5H), 3,99 (d, 1H), 3,51 (d, 1H), 3,37 (br s, 1H), 1,54 (s, 3H), 1,30 (s, 3H), 0,98 (d, 3H).
Anal. izračunato za C13H19Cl2NO2: C, 53,43; H, 6,55; N, 4,79. Ustanovljeno: C, 53,51; H, 6,58; N, 4,73.
[α]D20°C = +31,9° (0,64, 95% EtOH)
Apsolutna konfiguracija (+)-(2S,3S)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinola se odredi sljedećim kristalografskim postupkom pomoću x-zraka. Kristalni podaci: C13H18Cl2NO2, M=291, ortorompski, prostorna skupina P212121, a = 8,7348 (6), b = 14,9824 (10), c = 23,1605 (15) Å, V=3031 (4) Å3, Z=8, Dc=1,276 Mgm-3,F(000)=1226,95. Od 12224 izmjerenih refleksija, 3764 su bile jedinstvene i 2318, koje su imale I > 3,0σ(I), je upotrijebljeno u daljnjim izračunavanjima. Podaci su sakupljeni na Siemens SMART difraktometru pomoću omega skanova i monokromatskog MoKα zračenja (λ = 0,71073 Å). Položaji svih atoma, koji nisu vodik, su određeni direktnim postupcima i rafinirani anisotropski. Položaji vodika su svi određeni u različitim sintezama i uključeni u subsekventnim ciklusima rafiniranja upotrebom modela kretanja i idealizirane duljine veze od 0,96 Å. Apsolutna konfiguracija je određena rafiniranjem Rogersovih parametara i potvrđena analizom 185 najboljih Bijvoet razlika intenziteta koje su ukazale na vjerojatnost od 0,006 da je model pogrešan. Rafiniranjem pomoću najmanjih kvadrata je minimizirana Σw(ΔF)2, sa težinama baziranim na protivnoj statistici. Konačni faktori podudaranja su bili Rf = 0,064 (0,108 za sve podatke), Rw = 0,068 (0,081 za sve podatke), i GoF = 1,93. Reference uključuju E.J. Gabe, Y. Le Page, J.-P. Charland, F.L. Lee i P.S. White, Journal of Applied Crystallography, 22, 384-387 (1989 i D. Rogers, Acta Crystallographica, A37, 734-741, 1981.
Količina spoja formule (I) potrebna da se postigne željeni terapijski efekt će, naravno, ovisiti o određenom broju faktora, na primjer, načinu primjene, primatelju i stanju koje se liječi. Općenito, dnevna doza će se kretati u opsegu od 0,02 do 5,0 mg/kg. Određenije, opseg uključuje 0,02 do 2,5 mg/kg, 0,02 do 1,0 mg/kg, 0,02 do 0,25 mg/kg, 0,02 do 0,15 mg/kg i 0,02 do 0,07 mg/kg.
Spoj formule (I) se može upotrijebiti za liječenje depresije, hiperaktivnog poremećaja nedostatka pažnje (ADHD), pretilosti, migrene, boli, seksualne disfunkcije, Parkinsonove bolesti, Alzheimerove bolesti, ili ovisnosti o kokainu ili proizvodima koji sadrže nikotin (naročito duhan) kao spoj sam po sebi, ali je poželjno predstavljen s jednim ili više farmaceutski prihvatljivih nosača, razrjeđivača ili ekscipijenata u obliku farmaceutskog pripravka. Nosači, razrjeđivači i ekscipijenti moraju, naravno, biti prihvatljivi u tom smislu da su kompatibilni s ostalim sastojcima pripravka i ne smiju biti štetni za primatelja. Nosač mora biti krutina ili tekućina, ili oboje, ali se poželjno formulira sa sredstvom kao pripravak s jediničnom dozom, na primjer tableta.
Pripravci uključuju one koji su prikladni za oralnu, rektalnu, lokalnu, bukalnu (npr. sublingvalnu) i parenteralnu (npr. subkutanu, intramuskularnu, intradermalnu ili intravensku) primjenu.
Pripravci prikladni za bukalnu (sublingvalnu) primjenu uključuju bombone koje sadrže spoj formule (I) u aromatiziranoj bazi, obično saharoze i akacije ili traganta, i pastile koje sadrže sredstvo u inertnoj bazi kao npr. želatine i glicerina ili saharoze i akacije.
Pripravci iz ovog izuma prikladni za parenteralnu primjenu prikladno uključuju sterilne vodene pripravke spoja formule (I), poželjno izotonične sa krvi predviđenog primatelja. Ti pripravci se poželjno primjenjuju intravenski, iako se primjena može također provesti subkutanom, intramuskularnom, ili intradermalnom injekcijom. Takvi pripravci se mogu prikladno pripraviti miješanjem sredstva s vodom i steriliziranjem i izotonizacijom dobivene otopine.
Pripravci prikladni za rektalnu primjenu su poželjno predstavljeni kao supozitoriji s jediničnom dozom. Oni se mogu načiniti miješanjem spoja formule (I) s jednim ili više uobičajenih čvrstih nosača, na primjer, kakao maslacem, i zatim oblikovanjem dobivene smjese.
Pripravci prikladni za lokalnu primjenu na kožu poželjno imaju oblik masti, kreme, losiona, paste, gela, spreja, transdermalnog flastera, aerosola, ili ulja. Nosači koji se mogu upotrijebiti uključuju vazelin, lanolin, polietilen glikole, alkohole, i kombinacije dva ili više navedenih.
Trebalo bi razumjeti da, uz sastojke pojedinačno navedene iznad, pripravci mogu uključivati druga sredstva uobičajena u struci, s obzirom na tip pripravka o kojem se radi.
Biološka aktivnost spoja formule (I) je pokazana na in vitro modelima preuzimanja i modelu behavioralne depresije inducirane tetrabenazinom. Racemični morfolinol metabolit, (±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol, je dalje u tekstu označen kao “racemat”. (-) oblik morfolinol metabolita je (-)-(2R,3R)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol ili njegove farmaceutski prihvatljive soli i solvati, i označen je u tekstu kao spoj formule (II):
[image]
In vitro pokusi sinaptosomskog preuzimanja. In vitro preuzimanje je određeno kako je opisano ranije, pomoću sinaptosoma pripremljenih iz štakorskog kaudoputamena (za preuzimanje dopamina) i hipotalamusa (za preuzimanje NA i serotonina), upotrebom [3H]-dopamina, [3H]-NA i [3H]-serotonina kao transportnih supstrata, pojedinačno. Vidi Eckhardt, S.B., R.A. Maxwell, i R.M. Ferris, A Structure-Activity Study of the Transport Sites for the Hypothalamic and Striatal Catecholamine Uptake Systems. Similarities and differences. Molecular Pharmacology, 21: str. 374-9, 1982.
Sinaptosomi za upotrebu za dobivanje podataka o in vitro preuzimanju se priprave od hipotalamusa ili striatum-a blagim homogeniziranjem tkiva u 0,3M saharozi/25mM Tris pH 7,4 puferu koji sadrži iproniazid fosfat, za inhibiranje monoamin oksidaze. Homogenat se centrifugira na 1100 × g pri 4°C 10 min i supernatant se upotrijebi za studije preuzimanja. Supernatant (~1 mg tkivnih proteina) se inkubira sa Km koncentracijama [3H]-noradrenalina, [3H]-dopamina ili [3H]-serotonina pri 37 °C 5 minuta u modificiranom Krebs-Henseleit puferu (118 mM NaCl, 5 mM KCl, 25 mM NaHCO3, 1,2 mM NaH2PO4, 1,2 mM MgSO4, 11 mM dekstroze, 2,5 mM CaCl2) u odsutnosti i prisutnosti lijeka. U tim uvjetima preuzimanje je linearno s obzirom na supstrat i na tkivo (uz <5% ukupnog supstrata transportiranog). Ne-specifično preuzimanje je definirano kao preuzimanje pri 0°C. [3H]-supstrat, koji je transportiran u sinaptosome, se odijeli od slobodnog [3H]-supstrata filtracijom preko GF/B filtara i ispiranjem sa hladnim Krebs-Henseleit puferom. Izmjeri se tricij na filtrima u tekućinskom scintilacijskom spektrometru.
Podaci za in vitro sinaptosomsko preuzimanje su predstavljeni u tablici 1. Od 2 enantiomera morfolinol metabolita bupropiona, (+) enantiomer, spoj formule (I), je inhibirao preuzimanje noradrenalina (NA) sa IC50 od 2,2 µM. Suprotno, (-) enantiomer bio nedjelotvoran u koncentraciji od 30 µM. Za preuzimanje dopamina (DA), spoj formule (I) je imao IC50 od ~10 µM, dok je (-) enantiomer bio nedjelotvoran pri 30 µM. Nijedan spoj nije inhibirao preuzimanje serotonina pri 30 µM.
Za usporedbu, Wellbutrin® je bio ekvipotentan za inhibiranje preuzimanja DA i noradrenalina s IC50 vrijednostima od 1,9 i 2,2 µM, i nije inhibirao preuzimanje serotonina pri 30 µM. Imipramin (ne-specifični triciklički antidepresiv) je inhibirao preuzimanje NA i serotonina s IC50 vrijednostima od 0,072 i 0,24 µM, pojedinačno.
Spoj formule (I) je bio približno dvaput potentniji od Wellbutrina® kao NA inhibitor ali, za razliku od posljednjeg, bio je približno 10 puta manje potentan kao inhibitor preuzimanja dopamina. Ti podaci odgovaraju primijećenom noradrenergičkom djelovanju Wellbutrina® i racemičnog morfolinol metabolita bupropiona, (±)-(2R*,3R*)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol hidroklorida, (306U73) in vivo, u njihovom pojedinačnim anti-TBZ dozama (Cooper, B.R., i sur., Neuropsychopharmacology, 11: str. 133-42, 1994). Behavioralni i elektrofiziološki podaci sugeriraju da su učinci Wellbutrina® posredovani noradrenergičkim mehanizmom (prethodno citirano).
Pokusi behavioralne depresije inducirane tetrabenazinom. Behavioralna depresija inducirana tetrabenazinom je upotrijebljena kao in vivo mjera antidepresivnog djelovanja. Test je validiran na širokom rasponu antidepresiva, za koje je poznato da djeluju preko noradrenergičkih mehanizama (Cooper, B.R., i sur., “Animal models used in the prediction of antidepressant effects in man”, J. Clin. Psychiatry 44: 63-66, 1983). Dalje, test je također upotrijebljen za identifikaciju Wellbutrina® kao antidepresiva. Ukratko, životinjama se injicira sredstvo kandidat (p.o. ili i.p.) 30 minuta prije nego što prime i.p. injekciju tetrabenazina (35 mg/kg, kao HCl sol - pripravljen svježe za svaku upotrebu). Ispitivanja su provedena 30 minuta nakon toga i uključivala su: lokomotornu aktivnost (skala 1-4); ptozu (skala 1-4) i tjelesnu temperaturu, kako je ranije opisano (Cooper, B.R., J.L. Howard, i F.E. Soroko, Animal models used in prediction of antidepressant effects in man, Journal of Clinical Psychiatry,44: str. 63-6, 1983). U svim studijama, znanstvenici koji su provodili ispitivanja su bili “slijepi” za tretmane. Svi parametri su zajedno izvagani da daju “skupljeni” rezultat (X) pomoću sljedećeg algoritma:
X = (1+rezultat ptoze)/(rezultat aktivnosti*[temp,tretirana/temp,kontrola])
Rezultati iz modela behavioralne depresije inducirane tetrabenazinom su kako slijedi. Ispitani in vivo u koncentraciji od 25 mg/kg (ip) spoj formule (I), racemat, Wellbutrin® i, za usporedbu, amitriptilin, su svi poništili behavioralnu depresiju induciranu tetrabenazinom. Suprotno tome, (-) enantiomer je pokazao samo skromnu aktivnost (slika 1).
U TBZ modelu behavioralne depresije, aktivnost je bila u spoju formule (I). Kad je analizirana u studiji doza-učinak sa TBZ, aktivnost je pokazala oštro povećanje u aktivnosti između 3 mg/kg i 6 mg/kg (ip) (slika 2). Spoj formule II, za usporedbu, nije imao aktivnost povezanu sa dozom i, u koncentraciji od 50 mg/kg, izgleda da je pogoršao stanje životinje (slika 3). Na slikama 2 i 3, AMIT (5) se odnosi na amitriptilin u dozi od 5 mg/kg i SHAM se odnosi na kontrolnu skupinu životinja koje nisu primile nikakav lijek.
Budući da TBZ test predviđa antidepresive koji djeluju preko noradrenergičkih mehanizama i spoj formule (I) je inhibitor preuzimanja noradrenalina i Wellbutrin® se metabolizira do tog morfolinola in vivo, podaci ukazuju da antidepresivna aktivnost Wellbutrina® vjerojatno proizlazi iz učinaka spoja formule (I). (Welch, R.M., A.A. Lai, i D.H. Schroeder, Pharmacological significance of the species differences in bupropion metabolism. Xenobiotica, 17: str. 287-98, 1987).
Nadalje, druga djelovanja Wellbutrina® bi se mogla pripisati spoju formule (I). Naročito, noradrenergički mehanizam je uobičajen za sredstva koja se upotrebljavaju za tretiranje ADHD (npr. metilfenidat i amfetamin). Iako je molekularni mehanizam učinaka Wellbutrina na prestanak pušenja manje razumljiv, misli se da kateholaminergički put sudjeluje u behavioralnim pojačavajućim svojstvima nikotina. Wellbutrin® (i, u produžetku, spoj formule (I)), povećavanjem otpuštanja NA u moždane sinapse, mogu oponašati neka djelovanja nikotina i, na taj način, smanjiti simptome povezane sa povlačenjem nikotina. Dodatno, amfetamini su se upotrebljavali za liječenje pretilosti. Međutim, adiktivna svojstva amfetamina unaprijed isključuju njihovu upotrebu kod većine pretilih pacijenata. Wellbutrin® uzrokuje gubitak težine i, poput amfetamina, djeluje preko noradrenergičkog mehanizma. (Zarrindast, M.R. i T. Hosseini-Nia, Anorectic and behavioural effects of bupropion. General Pharmacology, 19: str. 201-4, 1988, i Harto-Truax, N. i sur., Effects of bupropion on Body Weight. Journal of Clinical Psychiatry, 44: str. 183-6, 1983). Međutim, za razliku od amfetamina, Wellbutrin® ne uzrokuje ovisnost. (Lamb, R.J. i R.R. Griffiths, Self-administration in Baboons and the Discriminative Stimulus Effects in Rats of Bupropion, Nomifensine, Diclofensine and Imipramine. Psychopharmacology, 102: str. 183-90, 1990; Bergman, J., i sur., Effects of Cocaine and Related Drugs in Nonhuman Primates. III. Self-administration by Squirrel Monkeys, Journal of Pharmacology & Experimental Therapeutics, 251: str. 150-5, 1989, i Johanson, C.E., i J.E. Barret, The Discriminative Stimulus Effects of Cocaine in Pigeons, Journal of Pharmacology & Experimental Therapeutics, 267: str. 1-8, 1993). U produžetku, očekivalo bi se da i spoj formule (I) bude djelotvoran kod pretilosti i ovisnosti o kokainu.
Liječenje ovisnosti o proizvodima koji sadrže nikotin uključuje djelomično i potpuno olakšanje od ovisnosti. Dakle, što se tiče duhanskih proizvoda, kao i prestanka aktivnosti, na primjer pušenja, to će također uključivati sniženje razine ili učestalosti takve aktivnosti, npr. smanjenje broja popušenih cigareta u danom periodu. Što se tiče ostalih proizvoda koji sadrže nikotin, tretman će također uključivati i prestanak i sniženje razine upotrebe takvih proizvoda.
Sigurnost i toksičnost. Provedene su dodatne studije variranja doza da se odredi opseg sigurnih doza za izomere i racemat. Životinje su bile promatrane da se uoči prisutnost ozbiljnih štetnih događaja (npr. napadaja i smrti) nakon primjene spojeva formule I, formule II, ili racemata oralnim i intraperitonejskim (i.p.) putem. Podaci su prikazani u tablici II.
Oralnom primjenom, u koncentraciji od 100 mg/kg p.o., napadaji su primijećeni kod spoja formule II i racemata, ali ne kod spoja formule I. Napadaji su primijećeni kod svih životinja za sva tri spoja kad su dozirani u koncentraciji od 300 mg/kg. Dodatno, 300 mg/kg oralna doza je rezultirala sa 100 i 80% letaliteta za spoj formule II i racemat, dok nije bilo smrti sa spojem formule I.
Primijenjeni i.p., svi spojevi su proizveli napadaje u koncentraciji od 100 mg/kg. Nisu primijećene smrti sa spojem formule I, dok su spoj formule II i racemat rezultirali letalitetom od 100% i 20% pojedinačno. U koncentraciji od 300 mg/kg oralne doze, letalitet je primijećen kod svih spojeva.
Tablica 1
Učinci na preuzimanje in vitro
Preuzimanje [3H]-dopamina
[image]
Preuzimanje [3H]-noradrenalina
[image]
Preuzimanje [3H]-serotonina
[image]
Tablica 2
Štetni događaji povezani sa spojevima formule I, formule II i racemata
[image] n/a označava da učinak nije primijećen i, prema tome, nije dan postotak
Claims (5)
1. Spojevi, naznačeni time, da su farmaceutski prihvatljive soli i solvati (+)-(2S,3S)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinola.
2. Spoj, naznačen time, da je (+)-(2S,3S)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol hidroklorid.
3. Spoj, naznačen time, da je (+)-(2S,3S)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol hidroklorid u izoliranom obliku.
4. Spoj, naznačen time, što je (+)-(2S,3S)-2-(3-klorfenil)-3,5,5-trimetil-2-morfolinol hidroklorid u optički čistom obliku.
5. Spoj prema jednom od zahtjeva 2 do 4, naznačen time, da ima specifičnu optičku rotaciju [α]D20 od +31,9° u 95% EtOH na c=0,64.
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