HRP20000809A2 - 2-(3,5-bis-trifluoromethyl-phenyl)-n-methyl-n-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide - Google Patents
2-(3,5-bis-trifluoromethyl-phenyl)-n-methyl-n-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide Download PDFInfo
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- HRP20000809A2 HRP20000809A2 HR20000809A HRP20000809A HRP20000809A2 HR P20000809 A2 HRP20000809 A2 HR P20000809A2 HR 20000809 A HR20000809 A HR 20000809A HR P20000809 A HRP20000809 A HR P20000809A HR P20000809 A2 HRP20000809 A2 HR P20000809A2
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- morpholin
- pyridin
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- C—CHEMISTRY; METALLURGY
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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Description
Predloženi izum odnosi se na spoj formule
[image]
i na njegove farmaceutski prihvatljive kiselinske adicijske soli.
Spoj formule I i njegove soli su karakterizirane dragocjenim terapeutskim svojstvima. Nađeno je da je spoj predloženog izuina visoko selektivan antagonist receptora neurokinina 1 (NK-1, tvar P). Tvar P je undekapeptid koji nastaje prirodno i spada u porodicu tahikininskih peptida, pri čemu su potonji tako nazvani zbog njihovog trenutnog kontrakcijskog djelovanja na ekstravaskularno glatko mišićno tkivo.
Receptor zu tvar P je član super porodice s G proteinom povezanih receptora.
Neuropeptidni receptor za tvar P (NK-1) je rasprostranjen u živčanom sistemu sisavaca (posebno u mozgu i spinalnim ganglijama), cirkulacijskom sistemu i u perifnim tkivima (posebno duodemu i jejunumu) i uključen je u reguliranje brojnih različitih bioloških procesa.
Središnje i periferno djelovanje tahikinske tvari P kod sisavaca bilo je povezano s brojnim upalnim stanjima koja uključuju migrenu, reumatoidni artritis, astmu, i upalnu crijevnu bolest kao i posredovanje emetičkog refleksa i modulaciju poremećaja središnjeg nervnog sistema (CNS) kao što je Parkinsonova bolest (Neurosci. Res., 1996, 7, 187-214), anksioznost (Can. J. Phys., 1997. 75, 612-621) i depresija (Science, 1998, 281, 1640-1645).
Dokaz za upotrebljivost antagonista tahikinin receptora kod bola, glavobolje, posebno migrene, Alzheimerove bolesti, multiple skleroze, ublažavanja odvikavanja od morfija, kardiovaskularnih promjena, edema, kao Što je edem uzrokovan toplinskom ozljedom, kronične upalne bolesti, kao što je reumatoidni artritis, astme/bronhijalne, hiper-reaktivnosti i drugih respiratornih bolesti, uključiv alergijski rinitis, upalnih bolesti crijeva, uključiv ulcerativni kolitis i Crohnovu bolest, ozljede oka i očne upalne bolesti, objavljen je u "Tachvkinin Receptor and Tachykinin Receptor Antagonists", J. Auton. Farmacol., 13,23-93,1993.
Nadalje, neurokinin 1 receptor antagonisti su bili razvijeni za liječenje brojnih fizioloških poremećaja povezanih sa suviškom ili neravnotežom tahikinina, posebno tvari P. Primjeri stanja, u kojima je bila uključena tvar P, uključuju poremećaje središnjeg nervnog sistema kao što je anksioznost, depresija i psihoze (WO 95/16679, WO 95/18124 i WO 95/23798).
Neurokinin-1 receptor antagonisti se nadalje mogu upotrijebiti za liječenje bolesti kretanja i induciranog povraćanja.
K tome, u The New England Journal of Medicine, Sv. 340, br. 3,190-195, 1999 bila je opisana redukcija sa cisplatinom inducirane emezije pomoću selektivnog neurokinin-1-receptor antagonista.
Upotrebljivost neurokinin 1 receptor antagonista za liječenje određenih oblika urinarne inkontinencije opisana je, nadalje, u Neuropeptides, 32(1), 1-49, (1998) i Eur. J. Farmacol., 383(3), 297-303, (1999).
Nadalje, US 5,972,938 opisuje metodu za liječenje psihoimunološkog ili psihosomatskog poremećaja davanjem tahikinin receptora, kao što je NK-1 receptor antagonist.
Life Sci. (2000), 67(9), 985-1001 opisuje, da astrociti umnažaju funkcionalne receptore za brojne neurotransmitere, uključiv i tvar P, koja je važan stimulans za reaktivne astrocite u razvoju CNS-a, kod infekcije i ozljede.
U moždanim tumorima, maligne glijalne stanice koje potječu od astrocita, aktiviraju se s tahikininima preko NK-1 receptora, čime se oslobađaju topivi medijatori i raste brzina njihove proliferacije. Zbog toga se selektivni NK-1 receptor antagonisti mogu upotrijebiti kao terapeutski pristup za liječenje malignih glioma kod liječenja raka.
U Nature (London) (2000), 405(6783), 180-183 opisano je da miševi s genetskim prekidom NK-1 receptora pokazuju gubitak svojstava morfina za ponovnom potrebom. Zbog toga se NK-1 receptor antagonisti mogu upotrijebiti za liječenje simptoma pri odvikavanju od droga kao što su opijati i nikotin i za smanjenje njihove zloupotrebe/želje.
Predmet predloženog izuma je spoj formule I i njegove farmaceutski prihvatljive soli, pripravljanje gore spomenutog spoja, lijekovi koji sadrže taj spoj i njihova proizvodnja, kao i upotreba gore spomenutog spoja za suzbijanje ili prevenciju bolesti, posebno bolesti ili poremećaja ranije navedene vrste ili za proizvodnju odgovarajućih lijekova.
Najpovoljnije indikacije u skladu s predloženim izumom su one koje uključuju poremećaje središnjeg nervnog sistema, na primjer liječenje ili prevenciju određenih depresivnih poremećaja, anksioznosti ili emezije, davanjem NK-1 receptor antagonista. Glavni depresivni dogođaj definiran je kao period od najmanje dva tjedna tijekom kojih u većini dana ili gotovo svaki dan postoji depresivno raspoloženje ili gubitak zanimanja ili zadovoljstva u svim, ili gotovo svim aktivnostima.
Kako je ovdje opisano, pojam "farmaceutski prihvatljivih kiselinskih adicijskih soli" obuhvaća soli s anorganskim i organskim kiselinama, kao što je solna kiselina, dušična kiselina, sumporna kiselina, fosforna kiselina, limunska kiselina, mravlja kiselina, fumarna kiselina, maleinska kiselina, octena kiselina, sukcinska kiselina, vinska kiselina, metansulfonska kiselina, p-toluensulfonska kiselina i slične.
Predloženi spoj formule I i njegove farmaceutski prihvatljive soli mogu se proizvesti metodama koje su poznate u struci, na primjer dolje opisanim psotupkom, koji uključuje
a) reakciju spoja formule
[image]
sa spojem formule
[image]
u spoj formule
[image]
i, po želji, pretvorbu dobivenog spoja u farmaceutski prihvatljivu kiselinsku adicijsku sol.
U skladu s inačicom a) postupka, DIPEA (N-etil-di-izopropilamine) se doda u mješavinu spoja formule II i spoja formule III u diklormetanu i smjesu se miješa pri temperaturi između 35-40°C. Željeni spoj formule 1 se dobije nakon čišćenja s dobrim iskorištenjem.
Sol se dobije pri sobnoj temperaturi u skladu s metodama koji kao takove poznati svakom stručnjaku. Moguće su ne samo soli s anorganskim kiselinama, već također i soli s organskim kiselinama. Primjeri takovih soli jesu hidrokloridi, hidrobromidi, sulfati, nitrati, citrati, acetati, maleati, sukcinati, metanesulfonati, p-toluen-sulfonati i slično.
Slijedeće sheme 1 i 2 i primjer 1 opisuju postupke za pripravljanje spoja formule 1 s više pojedinosti. Polazni materijali formula III, IV i VII su poznati spojevi i mogu se proizvesti u skladu s metodama koje su poznate u struci.
U slijedećim shemama upotrijebljene su slijedeće kratice:
PivCl pivaloil klorid
THF tetrahidrofuran
TMEDA N,N,N',N'-tetrametiletilen diamin
DIPEA N-etildiizopropil-amin
[image]
[image]
Kako je ranije spomenuto, spoj formule I i njegove farmaceutski upotrebljive adicijske soli imaju dragocjena farmakološka svojstva. Nađeno je, da je spoj predloženog izuma antagonist neurokinin 1 (NK-1, tvar P) receptora.
Spoj formule I ispitan je u skladu s pokusima datim ovdje u nastavku.
Afinitet spoja formule I za NKi receptor ocijenjen je na humanim NK1 receptorima u CHO stanicama inficiranim s humanim NK1 receptoroia (primjenom Semliki sistema ekspresije virusa) i radioobilježenog s [3h]-tvari P (krajnja koncentracija 0,6 nM). Pokusi vezanja provedni su u HEPES puferu (50 mM, pH 7,4) koji je sadržavao BSA (0,04%), leupeptin (8 μg/ml), MnCl2 (3 mM) i fosforamidon (2 μM). Za pokuse vezanja upotrijebljeno je 250 μl suspenzije membrana (1,25 x 105 stanica/ispitnoj epruveti), 0,125 μl pufera sredstva za premještanje i 125 μl [3H]-tvari P. Krivulje premještanja određene su s najmanje sedam koncentracija spoja. Ispitne epruvete su inkubirane 60 min pri sobnoj temperaturi i po isteku tog vremena sadržaji epruveta su brzo filtrirani pod vakuumom kroz GF/C filtere prethodno namakane 60 min u PEI (0,3%) s 2 x 2 ml pufera HEPES za ispiranje (50 mM, pH 7,4). Radioaktivnost zadržana na filterima je izmjerena pomoću scintilacijskog brojača. Svi ispitivanja su izvršeni po tri puta u najmanje 2 posebna pokusa.
Spoj formule I je jaki i selektivan antagonist za rekombinantne humane neurokinini (NKi) receptore ekspresionirane u CHO stanicama. On ima afinitet (pKi) od 9,0 za humani NK1 receptor iznad 2 reda magnitude selektivnosti za NK1 receptor, uspoređen prema NK2 i NK3 receptorima i uspoređen s više od 50 drugih mjesta vezanja koja su bila ocijenjena.
Djelovanje in vitro je ispitano proučavanjem učinka na ulaz Ca2+ induciran s tvari P u CHO stanice koje umnažaju rekombinantni humani NK1 receptor. U tim stanicama tvar P uzrokuje ulaz Ca2+ ovisan o koncentraciji, koji se može mjeriti primjenom FLIPR tehnologije. Povećanje koncentracije 2-(3,5-bis-trifluormetil-fenil)-N-metil-N-(6-morfolin-4-il-4-o-tolil-piridin-3-il)-izobutiramida uzrokuje pomak na desno u krivulji učinka koncentracije tvari P. Pomoću prikaza podataka na Schildovom dijagramu bilo je moguće izračunati antagonistički afinitet (pA2) za taj spoj od 8,9 (nagib Schildove regresije = 1,1). Ti podaci pokazuju da je 2-(3,5-bis-trifluormetil-fenil)-N-metil-N-(6-morfolin-4-il-4-o-tolil-piridin-3-il)-izobutir-amide kompetitivan antagonist na humanim rekombinantnim NKi receptorima.
In vivo spoj formule I antagonizira ponašanje tapkanja šapicom kod Gerbila inducirano s intracerebroventrikularnim (i.c.v.) injekcijama NK1 receptor agonista. Doza za ovaj spoj, izračunata tako da inhibira 50 % ponašanja tapkanja šapicom, nakon oralne aplikacije bila je 0,2 mg/kg. Količine u plazmi potrebne za potpuno antagoniziranje tog ponašanja su također bile izmjerene i nađena je ukupno pottrebna koncentracija u plazmi od 10 ng/ml za potpuno blokiranje ponašanja u smislu tapkanja šapicom. Taj antagonizam traje nekoliko sati i u ovom modelu je imao funkcionalno vrijeme trajanja od 8 sati.
2-(3,5-bis-trifluormetil-fenil)-N-metil-N-(6-morfolin-4-il-4-o-tolil-piridin-3-il)-izobutiramid je također ispitan kao antiemetičko sredstvo na Feretima. Emezija je inducirana u Feretima s raznim emetogenima (apomorfin, morfin, ipekakuanha, cisplatin i CuSO4. Prethodna obrada s tim spojem (0,3 mg/kg, p»o.) 2 sata prije emetigena, potpuno je blokirala emeziju induciranu sa svim emetogenima. Konstruirana je krivulja reakcije na punu dozu za emeziju induciranu s apomorfinom i izračunata je doza EDso od 0,1 mg/kg, p.o.
U modelu poremećenog kretanja na suncus murinus, nađeno je da spoj ima ED50 od 0,2 mg/kg, p.o.
Zbog toga, zaključno, 2-(3,5-bis-trifluormetil-fenil)-N-metil-N-(6-morfolin-4-il-4-o-tolil-piridin-3-il)-izobutir-amid je jaki antagonist ponašanja induciranog s NK1 kod Gerbila i on blokira emeziju kod Fereta i suncus munnus sličnom jačinom.
Farmakokinetički parametri su bili ocijenjeni u obadva slučaja, na štakorima i na psima. Kod štakora, spoj je imao vrijeme trajanja od 23 sata, vrijeme čišćenja od 4 ml/min/kg, volumnu razdiobu od 8 1/kg i oralnu biološku raspoloživost od 50%. Kod pasa, molekula je imala vrijeme trajanja od 40 sati, vrijeme čišćenja od 16 ml/min/kg, volumnu razdiobu od 22 l/kg i oralnu biološku raspoloživost od 30-40%.
Spoj formula I kao i njegove farmaceutski upotrebljive kiselinske adicijske soli mogu se upotrijebiti kao lijekovi, npr. u obliku farmaceutskih pripravaka. Farmaceutski pripravci se mogu dati oralno, npr. u obliku tableta, prevučenih tableta, dražeja, kapsula od tvrde i meke želatine, otopina/ emulzija ili suspenzija. Međutim, aplikacija se može izvršiti također i rektalno, npr. u obliku čepića, ili parenteralno, npr. u obliku injekcijskih otopina.
Spoj formule I i njegove farmaceutski upotrebljive kiselinske adicijske soli mogu se preraditi s farmaceutski inertnim, anorganskim ili organskim pomoćnim tvarima za proizvodnju tableta, prevučenih tableta, dražeja i kapsula od tvrde želatine. Kao takove pomoćne tvari npr. za tablete, dražeje i kapsule od tvrde želatine mogu se upotrijebiti laktoza, kukuruzni škrob ili njegovi derivati, talk, stearinska kiselina ili njene soli itd.
Prikladne pomoćne tvari za kapsule od meke želatine jesu npr. biljna ulja, voskovi, masti, polukruti i tekući polioli itd.
Prikladne pomoćne tvari za proizvodnju otopina i sirupa jesu npr. voda, polioli, saharoza, invertni šećer, glukoze itd.
Prikladne pomoćne tvari za injekcijske otopine jesu npr. voda, alkoholi, polioli, glicerol, biljna ulja itd.
Prikladne pomoćne tvari za čepiće jesu npr. prirodna ili otvrdnuta ulja, voskovi, masti, polutekući ili tekući polioli itd.
Osim toga, farmaceutski pripravci mogu sadržavati konzervanse, sredstva za pospješivanje otapanja, stabilizatore, sredstva za kvašenje, emulgatore, zaslađivače, bojila, začine, soli za mijenjanje osmotskog tlaka, pufere, sredstva za maskiranje ili antioksidante. Oni također mogu sadržavati i druge terapeutski vrijedne tvari.
Doziranje se može mijenjati u širokim granicama, i podešava se, naravno, prema pojedinačnim zahtjevima u svakom posebnom slučaju. Općenito, u slučaju oralnog davanja trebalo bi biti prikladno dnevno doziranje od pribl. 10 do 1000 mg po osobi spoja formule I, iako se gornju granicu može prekoračiti ako je potrebno.
Slijedeći primjer I prikazuje predloženi izum bez namjere da ga ograniči. Sve temperature su date u stupnjevima Celsiusa.
Primjer 1
2-(3,5-bis-trifluormetil-fenil)-N-metil-N-(6-morfolin-4-il-4-o-tolil-piridin-3-il)-izobutiramid hidroklorid (1:1,45)
a) 4-(5-nitro-2-piridil)-morfolin (XII)
K otopini od 20 g (126 mmolova) 2-klor-5-nitropiridina u 150 ml tetrahidrofurana doda se kao po kap tijekom 10 minuta 27 ml (315 mmolova) morfolina. Reakcijsku smjesu se refluktira još 2h. Kad se ohladi na sobnu temperaturu, otapalo se odstrani u vakuumu i ostatak se otopi u 200 ml etil acetata. Organsku fazu se ispere s 200 ml 1 N otopine natrijevog bikarbonata, osuši (magnezijev sulfat) i ispari, čime se dobije 27,3 g (kvantitativno) naslovnog spoja kao žute krute tvari. Talište 142-143°C.
b) 2,2-dimetil-N-(6-morfolin-4-il-piridin-3-il)-propionamid (V)
K otopini od 273 g (126 mmolova) 4-(5-nitro-2-piridil)-morfolina u 600 ml metanola doda se 2,5 g 10%-tnog paladija na aktiviranom ugljenu. Reakcijsku smjesu se hidrogenira (od sobne temperature do pribl. 45°C, 1 bar) dok se potroši teorijsku količinu vodika (pribl. 3h). Katalizator se odfiltrira i ispere se dva puta s obrocima od po 100 ml metanola. Filtrat se ispari u vakuumu, čime se dobije 22,6 g crvenog ulja koje, prema analizi pomoću tankoslojne kromatografije, sadrži pribl. 95% željenog derivata anilina.
Ovaj sirov proizvod se otopi u 240 ml tetrahidrofurana i 60 ml dietil etera. Kad se ohladi na 0°C, u jednom obroku se doda 26 ml (189 mmolova) trietilamina. Miješanje se nastavi i tijekom perioda od 10 minuta kap po kap doda se 23 g (189 mmolova) pivaloil klorida. Ledenu kupelj se odstrani i reakcijsku smjesu se miješa 1h pri sobnoj temperaturi. Zatim se otapalo odstrani u vakuumu i ostatak se suspendira u 200 ml 1 N otopine natrijevog bikarbonata. Proizvod se ekstrahira tri puta s obrocima od 200 ml diklormetana, osuši (natrijev sulfat) i ispari. Prekristalizacijom krutog ostatka iz etil acetat/heksana 1:8 dobiveno je 28,6 g (86%) naslovnog spoja kao bijelih kristala.
MS m/e (%) : 264 (M+H+, 100).
c) M-(4-jod-6-morfolin-4-il-piridin-3-il)-2,2-dimetil-propionamid (VI)
Otopinu od 28,4 g (108 mmol) 2,2-dimetil-N-(6-morfolin-4-il-piridin-3-il)-propionamida i 49 ml (324 mmola) N,N,N',N'-tetrametiletilendiamina pod argonom u 600 ml tetrahidrofurana ohladi se na kupelji suhog leda na -78°C. U roku od 1 sata, doda se kap po kap 202 ml (324 mmola) 1,6 N otopine n-butil-litija u heksanu. Reakcijsku smjesu se pusti zagrijati preko noći na -35°C. Ponovno se ohladi na -78°C i tijekom 15 minuta doda se kap po kap 37 g (146 mmolova) joda otopljenog u 60 ml tetrahidrofurana. Kupelj suhog leda se zamijeni s ledenom kupelji i tijekom 10 minuta doda se otopinu od 90 g (363 imnola) natrijevog tiosulfat pentahidrata u 250 ml vode kad temperatura reakcijske smjese dosegne 0°C. Zatim se doda 1000 ml dietil etera i organski sloj se odvoji. Vodeni sloj se ekstrahira dva puta s 500 ml diklormetana i sjedinjeni organski slojevi se osuše (magnezijev sulfat) i ispare. Vakuumskom kromatografijom dobiveno je 15,6 g (37%) naslovnog spoja kao svjetlo smeđeg ulja koje kristalizira nakon stajanja pri sobnoj temperaturi.
MS m/e (%): 389 (M+, 71), 358 (25), 304 (43), 57 (100).
d) 2,2-dimetil-N-(6-morfolin-4-il-4-o-tolil-pyridin-3-il)-propionamid (VIII)
Mješavinu od 3,50 g (9,0 mmolova) N-(4-iodo-6-morfolin-4-il-piridin-3-il)-2,2-dimetil-propionamida, 35 ml toluena, 18 ml 2 N otopine natrijevog karbonata, 312 mg (0,27 mmola) tetrakis(trifenilfosfin)paladija(0) i 1,34 g (9,9 mmolova) o-tolilborne kiseline grije se 12 sati pod argonom pri 80°C. Kad se ohladi na sobnu temperaturu, vodenu fazu se odvoji i ispere dva puta s etil acetatom. Sjedinjeni organski slojevi se isperu s 50 ml zasićene otopine NaCl, osuše (natrijev sulfate) i ispare. Čišćenjem vakuumskom kromatografijom dobiveno je 3,23 g (kvantitativno) naslovnog spoja kao bijele pjene.
MS m/e (%) : 354 (M+H+ 100).
e) 6-morfolin-4-il-4-o-tolil-piridin-3-ilamin (IX)
Suspenziju od 2,93 g (8,28 mmolova) 2,2-dimetil-N-(6-morfolin-4-il-4-o-tolil-piridin-3-il)-propionamida u 80 ml 3 N otopine solne kiseline i 5 ml 1-propanola grije se preko noći pri 90-95°C. Reakcijsku smjesu se ohladi na sobnu temperaturu, ispere s tri obroka po 20 ml dietil etera i filtrira preko celita. Filtrat se razrijedi s 20 ml vode i pH se namjesti na 7-8 dodatkom 28%-tne otopine natrijevog hidroksida uz hlađenje ledom. Proizvod se ekstrahira sa 4 obroka po 100 ml diklormetana. Sjedinjeni organski slojevi se isperu s 50 ml zas. otopine NaCl, osuše (magnezijev sulfat) i ispare, čime se dobije 2,31 g (kvantitativno) naslovnog spoja kao bijele pjene.
MS m/e (%) : 269 (M+, 100).
f) Metil-(6-morfolin-4-il-4-o-tolil-piridin-3-il)-amin (II)
Otopinu od 2,24 g (8,3 mmol) 6-morfolin-4-il-4-o-tolil-piridin-3-ilainina u 17 ml trimetil ortoformata i 3 kapi trifluoroctene kiseline grije se 2h pri 130°C. Reakcijsku smjesu se ispari i suši 30 minuta u vakuumu. Zaostalo ulje se otopi u 5 ml tetrahidrofurana i kap po kap uz hlađenje ledom doda se k 630 mg (16,6 mmolova) litij-aluminijevog hidrida u 20 ml tetrahidrofurana. Reakcijsku smjesu se miješa 1 sat pri sobnoj temperaturi, ohladi se ponovno na 0°C i zakiseli (pH 1-2) dodatkom 28%-tne otopine solne kiseline. Nakon 5 minuta miješanja, doda se 28%-tnu otopinu natrijevg hidroksida da se dosegne pH 10. Otopinu se filtrira preko celita, ispari i očisti vakuumskom kromatografijom, čime se dobije 1,56 g (66%) naslovnog spoja kao bijele pjene.
MS m/e (%): 283 (M% 100).
g) 2-(3,5-bis-trifluormetil-fenil)-N-metil-N-(6-morfolin-4-il-4-o-tolil-piridin-3-il)-izobutiramid (I)
Otopinu od 1,46 g (5,15 mmolova) metil-(6-morfolin-4-il-4-o-tolil-piridin-3-il)-amina i 1,32 ml (7,73 mmolova) N-etildiizopropilamina u 15 ml diklormetana se ohladi na lednoj kupelji i kap doda se 1,8 g (5,67 inmolova) 2-(3,5-bis-trifluormetil-fenil)-2-metil-propionil klorida. Reakcijsku smjesu se grije 3 sata pri 35-40°C, ponovno se ohladi na sobnu temperature i pomiješa se s 25 ml zasićene otopine natrijevog bikarbonata. Organski sloj se odvoji i vodenu fazu se ekstrahira s diklormetanom. Sjedinjeni organski slojevi se osuše (magnezijev sulfat) i ispare. Ostatak se očisti vakuumskom kromatografijom, čime se dobije 2,9 g (kvantitativno) naslovnog spoja kao bijelih kristala. Talište 131-132°C.
h) 2-(3,5-bis-trifluormetil-fenil)-N-metil-N-(6-morfolin-4-il-4-o-tolil-piridin-3-il)-izobutiramid hidroklorid(1:1,45)
K otopini od 2,9 g (5,13 mmolova) 2-(3,5-bis-trifluor-metil-fenil)-N-metil-N-(6-morfolin-4-il-4-o-tolil-piridin-3-il)-izobutiramida u 50 ml dietil etera uz hlađenje ledom doda se 2,8 ml 3 N otopine solne kiseline u dietil eteru. Miješa se 15 minuta pri 0°C, zatim se suspenziju ispari do suhog, i ponovno suspendira u 100 ml dietil etera, profiltrira i osuši u vakuumu, čime se dobije 2,82 g (89%) naslovnog spoja kao bijelih kristala. MS m/e (%) : 566 (M+HT', 100), 588 (M+Na+, 11).
Primjer A
Na uobičajen način prozvedene su tablete slijedećeg sastava:
mg/tableti
aktivna tvar 5
laktoza 45
kukuruzni škrob 15
mikrokristalinična celuloza 34
magnezijev stearat __1
težina tablete 100
Primjer B
Proizvedene su kapsule slijedećeg sastava:
mg/kapsuli
aktivna tvar 10
laktoza 155
kukuruzni škrob 30
talk __5
masa pune kapsule 200
Aktivna tvar, laktoza i kukuruzni škrob se najprije pomiješaju u mješalici, a zatim u stroju za usitnjavanje. Smjesu se vrati u mješalicu, doda se talk i temeljito se prmiješa. Smjesu se strojno puni u želatinske kapsule.
Primjer C
Proizvedeni su čepići slijedećeg sastava:
mg/čepiću
aktivna tvar 15
raasa čepića 1285
Ukupno 1300
Claims (11)
1. Spoj, naznačen time, da ima formulu
[image]
2. Spoj prema zahtjevu 1, naznačen time, da je to 2-(3,5-bis-trifluormetil-fenil)-N-metil-N-(6-morfolin-4-il-4-o-tolil-piridin-3-il)-izobutiramid.
3. Lijek, naznačen time, da sadrži spoj prema zahtjevima 1 i 2 i farmaceutski prihvatljiva pomoćna sredstva.
4. Lijek prema zahtjevu 3, naznačen time, da se upotrebljava za liječenje bolesti povezanih s NK-1 receptorom.
5. Postupak za proizvodnju spoj formule I definiranog kao u zahtjevu 1, naznačen time, da uključuje a) reakciju spoja formule
[image]
sa spojem formule
[image]
u spoj formule
[image]
i, po želji, pretvorbu dobivenog spoja u farmaceutski prihvatljivu kiselinsku adicijsku sol.
6. Spoj prema bilo kojem zahtjevu 1 i 2, naznačen time, da je proizveden postupkom prema zahtjevu 5 ili ekvivalentnom metodom.
7. Upotreba spoja formule I, naznačena time, da se on koristi za liječenje bolesti.
8. Upotreba spoja formule I prema zahtjevu 7, naznačena time, da se on koristi za liječenje bolesti povezanih s NK-1 receptorom.
9. Upotreba spoja formule I prema bilo kojem zahtjevu 1 i 2, naznačena time, da se on koristi za proizvodnju lijeka za liječenje bolesti povezanih s NK-1 receptorom.
10. Upotreba spoja formule I prema zahtjevu 9, naznačena time, da se on koristi za proizvodnju lijeka za liječenje depresije, anksioznosti ili emezije.
11. Izum, naznačen time, da je u skladu s gornjim opisom.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP99123685 | 1999-11-29 |
Publications (1)
| Publication Number | Publication Date |
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| HRP20000809A2 true HRP20000809A2 (en) | 2001-12-31 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| HR20000809A HRP20000809A2 (en) | 1999-11-29 | 2000-11-24 | 2-(3,5-bis-trifluoromethyl-phenyl)-n-methyl-n-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide |
Country Status (50)
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT1394150E (pt) * | 1999-02-24 | 2011-02-17 | Hoffmann La Roche | Derivados de 4-fenilpiridina e a sua utilização como antagonistas dos receptores de nc-1 |
| RU2238264C2 (ru) | 1999-02-24 | 2004-10-20 | Ф.Хоффманн-Ля Рош Аг | Производные бензола или пиридина и фармацевтическая композиция на их основе |
| SI1303490T1 (sl) * | 2000-07-14 | 2008-10-31 | Hoffmann La Roche | N-oksidi kot predzdravila NK 1 receptorskega antagonista 4-fenil-piridin derivatov |
| TWI287003B (en) * | 2000-07-24 | 2007-09-21 | Hoffmann La Roche | 4-phenyl-pyridine derivatives |
| TWI259180B (en) * | 2000-08-08 | 2006-08-01 | Hoffmann La Roche | 4-Phenyl-pyridine derivatives |
| US20030083345A1 (en) * | 2001-07-10 | 2003-05-01 | Torsten Hoffmann | Method of treatment and/or prevention of brain, spinal or nerve injury |
| MXPA04007353A (es) * | 2002-01-31 | 2004-11-26 | Hoffmann La Roche | Polimorfismos geneticos en gen de preprotaquikinina. |
| EP1643998B1 (en) | 2003-07-03 | 2007-08-29 | F. Hoffmann-La Roche Ag | Dual nk1/nk3 antagonists for treating schizophrenia |
| TWI280239B (en) | 2003-07-15 | 2007-05-01 | Hoffmann La Roche | Process for preparation of pyridine derivatives |
| MX2007000198A (es) | 2004-07-06 | 2007-03-15 | Hoffmann La Roche | Proceso para la preparacion de derivados de carboxamida-piridina utilizados como intermediarios en la sintesis de antagonistas del receptor nk-1. |
| CA2598762A1 (en) | 2005-02-25 | 2006-08-31 | F. Hoffmann-La Roche Ag | Tablets with improved drug substance dispersibility |
| ATE425144T1 (de) * | 2005-03-23 | 2009-03-15 | Hoffmann La Roche | Metaboliten für nk-i-antagonisten zur emesis |
| BRPI0616108A2 (pt) | 2005-09-23 | 2011-06-07 | Hoffmann La Roche | formulação de dosagem |
| EP2129381A1 (en) | 2007-01-24 | 2009-12-09 | Glaxo Group Limited | Pharmaceutical compositions comprising 3, 5-diamin0-6- (2, 3-dichl0phenyl) -l, 2, 4-triazine or r (-) -2, 4-diamino-5- (2, 3-dichlorophenyl) -6-fluoromethyl pyrimidine and an nk1 |
| US8426450B1 (en) | 2011-11-29 | 2013-04-23 | Helsinn Healthcare Sa | Substituted 4-phenyl pyridines having anti-emetic effect |
| KR101971385B1 (ko) | 2013-03-15 | 2019-04-22 | 글로벌 블러드 테라퓨틱스, 인크. | 헤모글로빈 조정을 위한 화합물 및 이의 용도 |
| CN105745198B (zh) | 2013-11-08 | 2018-09-21 | 橘生药品工业株式会社 | 羧甲基哌啶衍生物 |
| AU2015214182B2 (en) | 2014-02-07 | 2020-04-30 | Global Blood Therapeutics, Inc. | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
| TWI649307B (zh) | 2014-05-07 | 2019-02-01 | 日商橘生藥品工業股份有限公司 | Cyclohexylpyridine derivative |
| KR101948238B1 (ko) | 2016-08-19 | 2019-02-14 | (주)케어젠 | 미녹시딜과 펩타이드의 결합체 |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1082959A1 (en) * | 1991-09-20 | 2001-03-14 | Glaxo Group Limited | NK1 Antagonists for the treatment of depression |
| CA2099233A1 (en) * | 1992-06-29 | 1993-12-30 | Conrad P. Dorn | Morpholine and thiomorpholine tachykinin receptor antagonists |
| IL111960A (en) * | 1993-12-17 | 1999-12-22 | Merck & Co Inc | Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them |
| SG52217A1 (en) * | 1993-12-29 | 1998-09-28 | Merck Sharp & Dohme | Substituted morpholine derivatives and their use as therapeutic agents |
| IL112778A0 (en) * | 1994-03-04 | 1995-05-26 | Merck & Co Inc | Substituted heterocycles, their preparation and pharmaceutical compositions containing them |
| ES2194937T3 (es) * | 1995-03-24 | 2003-12-01 | Takeda Chemical Industries Ltd | Compuestos ciclicos, su produccion y uso como antagonistas de los receptores de taquiquinina. |
| US5972938A (en) * | 1997-12-01 | 1999-10-26 | Merck & Co., Inc. | Method for treating or preventing psychoimmunological disorders |
| PT1394150E (pt) * | 1999-02-24 | 2011-02-17 | Hoffmann La Roche | Derivados de 4-fenilpiridina e a sua utilização como antagonistas dos receptores de nc-1 |
| US6303790B1 (en) * | 1999-11-29 | 2001-10-16 | Hoffman-La Roche Inc. | Process for the preparation of pyridine derivatives |
| SI1303490T1 (sl) * | 2000-07-14 | 2008-10-31 | Hoffmann La Roche | N-oksidi kot predzdravila NK 1 receptorskega antagonista 4-fenil-piridin derivatov |
| TWI287003B (en) * | 2000-07-24 | 2007-09-21 | Hoffmann La Roche | 4-phenyl-pyridine derivatives |
| TWI259180B (en) * | 2000-08-08 | 2006-08-01 | Hoffmann La Roche | 4-Phenyl-pyridine derivatives |
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2000
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