HRP20000524A2 - Gylcine transport inhibitors - Google Patents

Gylcine transport inhibitors Download PDF

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Publication number
HRP20000524A2
HRP20000524A2 HR20000524A HRP20000524A HRP20000524A2 HR P20000524 A2 HRP20000524 A2 HR P20000524A2 HR 20000524 A HR20000524 A HR 20000524A HR P20000524 A HRP20000524 A HR P20000524A HR P20000524 A2 HRP20000524 A2 HR P20000524A2
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HR
Croatia
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formula
alkyl
represents hydrogen
radical
aryl
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HR20000524A
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English (en)
Inventor
Walter Herman Maria Lou Luyten
Frans Eduard Janssens
Ludo Edmond Josephine Kennis
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Janssen Pharmaceutica Nv
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Publication of HRP20000524A2 publication Critical patent/HRP20000524A2/hr

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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
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Description

Predloženi izum odnosi se na upotrebu α,α-difenil-1-piperidinbutanamida, koji inhibiraju transport glicina, za proizvodnju lijekova za liječenje poremećaja središnjeg i perifernog živčanog sistema, posebno psihoza, bola, epilepsije, neurodegenerativnih bolesti (Alzheimerove bolesti), kapi, traume glave, multiple skleroze i sličnog. Izum nadalje obuhvaća nove spojeve, njihovu proizvodnju i njihove farmaceutske oblike.
N,N-dimetil-α,α-difenil-1-piperidinbutanamidi, kao 4-(4-klorfenil)-4-hidroksi-N,N-dimetil-α,α-difenil-1-piperidinbutanamid (loperamid, ImodiumTM), su dobro poznati proizvodi protiv diareje. Ovi spojevi, njihovo djelovanje i pripravljanje opisani su najprije u US-3,714,159.
Predloženi izum odnosi se na upotrebu spojeva koji inhibiraju transport glicina za proizvodnju lijekova za liječenje poremećaja središnjeg i perifernog živčanog sistema, pri čemu spomenuti spojevi imaju formulu
[image]
njihovih N-oksida, stereokemijski izomernih oblika ili njihovih farmaceutski prihvatljivih adicijskih soli, u kojoj formuli
svaki od R1 i R2 neovisno predstavlja vodik ili C1-4;alkil;
X je radikal formule
[image]
u kojoj
crtkana linija predstavlja proizvoljnu vezu;
[image] R3 predstavlja radikal formule
[image]
u kojoj
svaki od R i R7 neovisno predstavlja vodik ili se obadva mogu uzeti zajedno s ugljikovim atomima na koje su vezani tako da se dobije fenilni prsten;
R8 predstavlja vodik ili halogen;
n je 1 ili 2;
R4 predstavlja vodik, hidroksi, C1-4-alkiloksi, C1-4-alkiloksi-C1-4-alkil ili C1-4-alkiloksi;
R5 predstavlja diarilmetiloksi-C1-4-alkil ili radikal formule
[image]
[image]
u kojoj
B1 predstavlja -CH2, -CH(OH)-, -NH-, -CH2-NH- ili izravnu vezu;
B2 predstavlja -NH-, -CH2 ili izravnu vezu;
B3 predstavlja -NR12 -, -CH2-, -C(=O) ili izravnu vezu;
B7 predstavlja -C1-4-alkandiil-NH- ili -NH-C1-4-alkil;
B8 predstavlja -NR19-, -CH2- ili -CH(aril)-;
svaki Y neovisno predstavlja O ili S;
-a1=a2-a3=a4- predstavlja dvovalentni radikal formule
-CH=CH-CH=CH- (b-1-a) ili
-NH=CH-N=CH- (b-1-b);
u kojoj vodikov atom u radikalu (b-1-a) može biti zamijenjen s hidroksi;
R9 predstavlja C1-4-alkil; ili C1-4-alkil supstituiran s arilom, tienilom, furanilom, furanil supstituiran s hidroksi-C1-4-alkilom, ili tiazolil;
R10 predstavlja aril, arilamino, C1-4-alkilamino, C1-4-alkiltio;
R11 predstavlja vodik, C1-4-alkil, halogen ili trifluor-metil;
R12 predstavlja vodik ili C1-4-alkilkarbonil;
R13 predstavlja vodik, C1-4-alkil ili aril;
R14 predstavlja vodik ili halogen;
svaki od R15 i R16 neovisno predstavlja vodik ili aril;
R17 predstavlja vodik ili C1-4-alkil;
R18 predstavlja aril, 10,11-dihidro-5H-dibenzo[b,f]-azepin-5-il ili C1-4-alkil prema potrebi supstituiran s jednim ili dva supstituenta od kojih je svaki neovisno odabran između C3-7-cikloalkila ili arila;
R19 predstavlja vodik, C1-4-alkilkarbonil ili diaril-C1-4-alkil;
svaki od R20, R21, R22 i R23 neovisno predstavlja vodik, C1-4-alkil ili aril;
R24 predstavlja vodik ili trifluormetil;
R25 predstavlja vodik ili halogen; i u slučaju da R5 predstavlja radikal formule (b-3), tada R4 također može biti fenil-C1-4-alkilaminokarbonil; i
R4 i R5 se mogu uzeti zajedno tako da tvore spiro radikal formule
[image]
u kojoj
svaki od R26 i R27 neovisno predstavlja vodik, C1-4-alkil, aril ili aril-C1-4-alkil;
aril predstavlja fenil, ili fenil supstituiran s 1 ili 2 supstituenta neovisno odabrana između C1-4-alkila, halogenog, trifluormetila, hidroksi i C1-4-alkoksi.
Predloženi izum odnosi se također na metodu za liječenje toplokrvnih bića koja pate od poremećaja središnjeg i perifernog živčanog sistema, posebno psihoza, bola, epilepsije, neurodegenerativnih bolesti (Alzheimerove bolesti), kapi, traume glave, multiple skleroze i sličnog. Spomenuta metoda uključuje davanje terapeutski učinkovite količine spoja formule (I) ili njegovog N-oksida, farmaceutski prihvatljive kiselinske ili bazične adicijske soli ili njegovog stereokemijski izomernog oblika s farmaceutskim nosačem.
Kako se rabi u gornjim definicijama i u nastavku, halogen se odnosi na fluor, klor, brom i jod; C3-7-cikloalkil odnosi se na ciklopropil, ciklobutil, ciklopentil, cikloheksil i cikloheptil; C1-4-alkil definira ravan i razgranati lanac zasićenih ugljikovodičnih radikala koji imaju od 1 do 4 ugljikova atoma, kao što su, na primjer, metil, etil, propil, butil, 1-metiletil, 2-metil-propil, 2,2-dimetiletil i slično; C1-4-alkandiil definira dvovalentan ravan i razgranati lanac zasićenih ugljikovodičnih radikala koji imaju od 1 do 4 ugljikova atoma, kao što su, na primjer, 1,1-metandiil, 1,2-etandiil, 1,3-propandiil, 1,4-butandiil, 1,2-propandiil, 2,3-butandiil i slično.
Podrazumijeva se da gore spomenute farmaceutski prihvatljive adicijske soli obuhvaćaju terapeutski aktivne oblike netoksičnih bazičnih ili kiselinskih soli koje mogu oblikovati spojevi formule (I). Oblik kiselinske adicijske soli spoja formule (I), koji nastaje u svom slobodnom obliku kao baza, može se dobiti obradom spomenute slobodne baze s odgovarajućom kiselinom, kao što je anorganska kiselina, na primjer halogenovodična kiselina, npr. solna kiselina ili bromovodična kiselina, sumporna kiselina, fosforna kiselina, i slične kiseline; ili organska kiselina kao na primjer octena, hidroksioctena, propionska, mliječna, piruvinska, oksalna, malonska, sukcinska, maleinska, fumarna, jabučna, vinska, limunska, metansulfonska, etansulfonska, benzensulfonska, p-toluensulfonska, ciklaminska, salicilna, p-aminosalicilna, pamoinska i slične kiseline.
Spojevi formule (I) koji sadrže kisele protone mogu se prevesti u njihove terapeutski aktivne netoksične baze, tj. oblike adicijskih soli metala ili amina, obradom s odgovarajućim organskim ili anorganskim bazama. Prikladni oblici bazičnih soli uključuju, na primjer, amonijeve soli, soli alkalijskih i zemno alkalijskih metala, npr. soli litija, natrija, kalija, magnezija, kalcija i slično, soli s organskim bazama, npr. soli benzatina, N-metil-D-glukamina, hidrabamina, i soli s amino kiselinama kao što su, na primjer, arginin, lizin i slično.
Obrnuto, spomenuti oblici soli mogu se prevesti u slobodne oblike obradom s odgovarajućom bazom ili kiselinom.
Pojam adicijske soli, kako se gore rabi, također uključuje solvate koje mogu oblikovati spojevi formule (I) kao i njihove soli. Takovi solvati jesu na primjer hidrati, alkoholati i slično.
Smatra se da N-oksida spojeva formule (I) uključuju one spojeve formule (I) u kojima je piperidinski dušikov atom oksidiran u N-oksid.
Pojam "stereokemijski izomernih oblika", kako se ovdje rabi, definira sve moguće stereoizomerne oblike spojeva formule (I). Ako nije spomenuto ili navedeno drugačije, kemijska oznaka spoja označava smjesu, a posebno racemičnu smjesu svih mogućih stereokemijski izomernih oblika, pri čemu spomenuta smjesa sadrži sve diastereomere i enantiomere osnovne molekulske strukture. Stereokemijski izomerni oblici spojeva formule (I) i smjese takovih oblika očigledno su obuhvaćene formulom (I).
Posebno, spojevi formule (I) i neki njihovi intermedijati imaju u svojoj strukturi najmanje jedno stereogeno središte. To stereogeno središte može biti prisutno u R ili S konfiguraciji, pri čemu se oznake S i R upotrebljavaju u skladu s pravilima opisanim u Pure Appl. Chem., 1976, 45, 11-30.
Neki spojevi formule (I) također mogu postojati u njihovim tautomernim oblicima. Iako nisu posebno navedeni u gornjoj formuli, takovi oblici se smatraju uključenim u opseg smisla predloženog izuma.
Kad se u nastavku koristi pojam spojeva formule (I), pri tome se misli da su također uključeni N-oksidi, farmaceutski prihvatljive adicijske soli i svi stereoizomerni oblici.
Predloženi spojevi formule (I) smatraju se novima pod uvjetom kad R4 predstavlja vodik i R5 je radikal formule (b-1), u kojoj B1 predstavlja -CH2- i R9 je 4-fluorbenzil, tada je –a1=a2-a3=a4- različit od -CH=CH-CH=CH-; i ako R4 predstavlja vodik i R5 je radikal formule (b-1), u kojoj B1 predstavlja -NH- i R9 je 4-metoksibenzil, tada je –a1=a2-a3=a4- različit od -CH=N-CH=CH-. Predloženi izum također se odnosi na upotrebu spomenutih novih spojeva formule (I) kao lijeka.
Povoljno, R5 predstavlja diarilmetiloksi-C1-4-alkil ili radikal formule (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), (b-8), (b-9), (b-10), (b-11), (b-12) ili (b-13); ili R5 se može uzeti zajedno s R4 tako da tvore spiro radikal formule (b-14).
Zanimljiva skupina spojeva su oni spojevi formule (I) u kojoj R1 i R2 predstavljaju metil.
Posebni spojevi su oni spojevi formule (I), u kojoj X predstavlja radikal formule (a), detaljnije, radikal formule (a) u kojoj R6 i R7, uzeti zajedno s dva ugljikova atoma na koje su vezani, tvore fenilni prsten.
Drugi posebni spojevi su oni spojevi formule (I) u kojoj X predstavlja radikal formule (b), u kojoj R5 predstavlja radikal formule (b-1), i ponajprije, R9 predstavlja C1-4-alkil supstituiran s arilom, naročito oni u kojima R9 predstavlja 4-fluorbenzil.
Također drugu skupinu posebnih spojeva čine oni spojevi formule (I) u kojoj X predstavlja radikal formule (b) u kojoj R5 predstavlja radikal formule (b-2), a ponajprije Y je S.
Prednosni spojevi jesu:
4-(11,12-dihidro-6H-benzimidazo[2,1-b][3]benzazepin-6-il)-N,N-dimetil-α,α-difenil-1-piperidinbutanamid;
4-[[1-[(4-fluorfenil)metil]-1H-benzimidazol-2-il]-hidroksimetil]-N,N-dimetil-α,α-difenil-1-piperidinbutanamid;
N-oksidi, stereokemijski izomerni oblici i njihove farmaceutski prihvatljive adicijske soli.
Općenito, spojevi formule (I) mogu se proizvesti u skladu s reakcijskim postupcima koji su opisani u US 3,714,159, US-4,695,575 i US-5,008,268, pobliže, reakcijom intermedijata formule (II), u kojoj W predstavlja prikladni suprotni ion kao, na primjer, halogen, ili njegov funkcionalni derivat, s intermedijatom formule (III).
[image]
Spomenuta reakcija može se provesti u reakcijski inertnom otapalu, kao što je, na primjer, metilizobutil keton, N,N-dimetilacetamid ili N,N-dimetilformamid, u prisutnosti prikladne baze, kao što je, na primjer, natrijev karbonat, natrijev bikarbonat ili trietilamin, i prema potrebi u prisutnosti kalijevog jodida.
U ovoj, i slijedećim pripravama, reakcijski proizvodi se mogu izolirati iz reakcijskog sredstva i, ako je potrebno, mogu se dalje očistiti u skladu s metodologijama koje su općenito poznate u struci kao, na primjer, ekstrakcijom, kristalizacijom, destilacijom, trituriranjem i kromatografijom.
Spojevi formule (I) mogu se također pretvoriti jedan u drugi postupcima transformacije funkcionalne skupine, koji postupci su poznati u struci.
Spojevi formule (I) mogu se također prevesti u odgovarajuće oblike N-oksida postupcima koji su u struci poznati pri pretvorbi trovalentnog dušika u oblik njegovog N-oksida. Spomenuta reakcija N-oksidacije može se općenito provesti reakcijom polaznog materijala formule (I) s 3-fenil-2- (fenilsulfonil)oksaziridina ili s odgovarajućim organskim ili anorganskim peroksidom. Prikladni anorganski peroksidi uključuju, na primjer, vodikov peroksid, perokside alkalijskih metala ili zemno alkalijskih metala, npr. natrijev peroksid, kalijev peroksid; prikladni organski peroksidi mogu uključiti peroksi kiseline, kao što je, na primjer, benzenkarboperoksi kiselina ili s halogenim supstituirana benzenkarboperoksi kiselina, npr. 3-klor-benzenkarboperoksi kiselina, peroksialkanske kiseline, npr. peroksioctena kiselina, alkilhidroperokside, npr. t-butil hidroperoksid. Prikladna otapala jesu, na primjer, voda, niži alkanoli, npr. etanol i slično, ugljikovodici, npr. toluen, ketoni, npr. 2-butanon, halogenirani ugljikovodoci, npr. diklormetan, i mješavine takovih otapala.
Neki spojevi formule (I) i neki intermedijati u predloženom izumu mogu imati nesimetričan ugljikov atom. Stereokemijski čisti izomerni oblici spomenutih spojeva i intermedijata mogu se dobiti primjenom poznatih postupaka. Na primjer, diastereoizomeri se mogu rastaviti fizičkim metodama, kao što je selektivna kristalizacija, ili kromatgrafskim postupcima, npr. razdiobom u suprotnoj struji, tekućinskom kromatografijom i sličnim metodama. Enantiomerni se mogu dobiti iz racemičnih smjesa najprije pretvorbom racemičnih smjesa s prikladnim sredstvima za ponovno otapanje, kao što su, na primjer, kiralne kiseline, da se dobiju smjese diastereomernih soli ili spojeva; zatim fizičkim rastavljanjem spomenute smjese diastereomernih soli ili spojeva na primjer selektivnom kristalizacijom ili kromatografskim postupcima, npr. tekućinskom kromatografijom i sličnim metodama; i konačno, pretvorbom spomenutih rastavljenih diastereomernih soli ili spojeva u odgovarajuće enantiomere. Čisti stereokemijski izomerni oblici također se mogu dobiti iz čistih stereokemijski izomernih oblika odgovarajućih intermedijata i polaznih materijala, pod uvjetom da se reakcije između njih odvijaju stereospecifično.
Alternativni način rastavljanja enantiomernih oblika spojeva formule (I) i intermedijata uključuje tekućinsku kromatografiju, posebno tekućinsku kromatografiju upotrebom kiralne štacionarne faze.
Neki intermedijati i polazni materijali su poznati spojevi i mogu se komercijalno dobiti ili se mogu proizvesti u skladu s poznatim postupcima.
Glicin je amino kiselinski neurotransmiter u središnjem i perifernom živčanom sistemu, u obadva slučaja na inhibicijskim i ekcitacijskim sinapsama. Te posebne funkcije glicina posreduju dva tipa receptora, od kojih je svaki povezan s drugačijim razredom transportera glicina. Inhibicijska djelovanja glicina posreduju receptori glicina koji su osjetljivi prema konvulzant.nom alkaloidu strihninu, i koji se zbog toga navode kao "strihnin-osjetljivi". Strihnin-osjetljivi receptori glicina nadeni su pretežno u kičmenoj moždini i korijenu mozga.
Glicin djeluje u ekcitatorskoj transmisiji modulacijom djelovanja glutamata, glavnog ekcitatorskog neurotransmitera u živčanom sistemu (Johnson i Ascher, Nature, 325, 529-531 (1987); Fletscher et al., Glycine Transmission, (Otterson i Strom-Mathisen, izd., 1990, str. 193-219). Specifično, glicin je obavezan ko-agonist u razredu glutamin receptora koji je nazvan N-metil-D-aspartat (NMDA) receptor. NMDA receptori su široko rasprostranjeni u mozgu, s posebno visokom gustoćom u cerebralnom korteksu u hipokampalnoj formaciji.
Transporteri uzimaju neurotransmiter sa sinapse, čime reguliraju koncentraciju i vrijeme neurotransmitera u sinapsi, što zajedno određuje magnitudu sinaptičke transmisije. Prevencijom širenja neurotransmitera na susjedne sinapse, transporteri zadržavaju točnost sinaptičke transmisije. Konačno, ponovnim uzimanjem oslobođenog transmitera u presinaptički terminal, transporteri dopuštaju ponovno korištenje transmitera. Transport neurotransmitera ovisan je o vanstaničnom natriju i razlici napona kroz membranu. Pod specifičnim uvjetima, na primjer tijekom napadaja, transporteri mogu funkcionirati u obratnom smjeru, oslobađajući neurotransmiter izvan stanice na način ovisan o kalciju (Attwell et al., Neuron, 11, 401-407 (1993)). Modulacija transportera neurotransmitera stoga osigurava sredstvo za modifikaciju sinaptičkog djelovanja, koje pruža korisnu terapiju za liječenje smetnji središnjeg i perifernog nervnog sistema.
Molekularnim kloniranjem otkriveno je postojanje dvaju razreda transportera glicina, nazvanih GlyT-1 i Gly-t2. Gly-T-1 je nađen pretežno u prednjem mozgu, i njegova razdioba odgovara razdiobi glutamatergnih staza i NMDA receptora (Smith, et al., Neuron, 8, 927-935 (1992)). Poznate su najmanje tri povezane inačice Gly-T-, naime GlyT-1a, GlyT-1b i GlyT-1c (Kim, et al., Molecular Pharmacology, 45, 608-617 (1994)), od kojih svaka pokazuje jedinstvenu razdiobu u mozgu i u perifernom tkivu. Suprotno tome, GlyT-2 je nađen pretežno u korijenu mozga i kičmenoj moždini, i njegova razdioba odgovara razdiobi prema strihninu osjetljvih receptora glicina (Liu, et al., J. Biological Chemistry, 268, 22802-22808 (1993); Jursky i Nelson, Neurochemistry, 64, 1026-1033 (1995)). Stoga se, dakle, može očekivati da se regulacijom sinaptičkih razina glicina, GlyT-1 i GlyT-2, može selektivno modulirati djelovanje NMDA receptora, odnosno receptora glicina osjetljivih prema strihninu.
Od spojeva koji inhibiraju ili aktiviraju transportere glicina može se stoga očekivati da mijenjaju funkciju receptora i time osiguravaju terapeutske prednosti u nizu bolesnih stanja. Stoga se, dakle, inhibicija GlyT-2 može primijeniti za slabljenje djelovanja djelovanja neurona koji imaju receptore glicina osjetljive prema strihninu povećanjem sinaptičkih razina glicina i tako oslabiti transmisiju informacije povezane s bolom (tj. nociceptivne) u kičmenoj moždini, za koju se je pokazalo da ju posreduju ti receptori. Yaksh, Pain, 37, 111-123 (1989). K tome, pojačavanje inhibicijske glicinergne transmisije s receptorima glicina osjetljivim prema strihninu u kičmenoj moždini može se primijeniti za smanjenje mišićne hiperaktivnosti, koja je korisna u liječenju bolesti ili stanja povezanih s povećanom kontrakcijom mišića, kao što je spazmatičnost, mioklonus i epilepsija (Troung et al., Movement Disorders, 3, 77-87 (1988); FASEB J, 4, 2767-2774 (1990)). Spastičnost, koja se može liječiti modulacijom receptora glicina, povezana je s epilepsijom, kapi, traumom glave, multiplom sklerozom, povredom kičmene moždine, distonijom, i drugim stanjima bolesti ili povreda živčanog sistema.
NMDA receptori su uključeni u pamćenje i učenje (Rison and Stanton, Neurosci. Biobehev. Rev., 19, 533-552 (1995);
Danysz et al., Behavioral Pharmacol., 6, 455-474 (1995)); i čini se da smanjena funkcija s NMDA posredovane transmisije doprinosi simptomima šizofrenije (Olney i Farber, Archives General Psychiatry, 52, 998-1007 (1996). Stoga se, dakle, sredstva koja inhibiraju GlyT-1 i time povisuju glicinsku aktivaciju NMDA receptora, mogu upotrijebiti kao nova antipsihotička i antidemencijska sredstva, te za liječenje drugih bolesti u kojima su suženi spoznajni procesi, kao što su poremećaj nedostatka pažnje i organski moždani sindromi. Obrnuto, prekomjerna aktivacija NMDA receptora bila je uključena u brojna bolesna stanja, posebno neuronsku smrt povezanu s kapi, traumom glave i vjerojatno kod neurodegenerativnih bolesti kao što je Alzheimerova bolest, multi-infarktna demencija, AIDS demencija, Huntigtonova bolest, Parkinsonova bolest, amiotrofička lateralna skleroza ili druga stanja u kojima dolazi do neuronske smrti stanica. Coyle & Puttfarcken, Science, 262, 689-695 (1993); Lipton i Rosenberg, New Engl. J. of Medicine, 330, 613-622 (1993); Choi, Neuron 1, 623-634 (1988). Stoga, dakle, farmakološka sredstva koja povisuju djelovanje GlyT-1, imat će za posljedicu smanjenje glicinske aktivacije NMDA receptora, čije djelovanje se može primijeniti za liječenje tih i srodnih bolesnih stanja. Slično tome, lijekovi koji izravno blokiraju glicinsku stranu NMDA receptora, mogu se upotrijebiti za liječenje tih i srodnih bolesnih stanja.
U svrhe aplikacije, predmetni spojevi se mogu formulirati u razne farmakološke sastave koji uključuju farmakološki prihvatljiv nosač, i kao aktivan sastojak sadrže terapeutski učinkovitu količinu novog spoja formule (I). Za pripravljanje farmaceutskih sastava prema izumu, učinkovitu količinu dotičnog spoja, dodatno soli ili u obliku slobodne baze, kao aktivan sastojak pomiješa se temeljito u smjesu s farmaceutski prihvatljivim nosačem, koji može imati vrlo različite oblike ovisno o obliku pripravka željenog za davanje. Ti farmaceutski sastavi su poželjni u obliku jedinstvenog doziranja, ponajprije za oralno, perkutano ili davanje parenteralnom injekcijom. Na primjer, za pripravljanje sastava u obliku oralnog doziranja, u slučaju tekućih pripravaka kao što su suspenzije, sirupi, eliksiri i otopine, može se upotrijebiti bilo koje uobičajeno farmaceutsko sredstvo, kao na primjer voda, glikoli, ulja, alkoholi i slično; ili u slučaju pudera, pulila, kapsula i tableta, mogu se upotrijebiti kruti nosači kao škrobovi, šećeri, kaolin, lubrikanti, veziva, sredstva za dezintegraciju i slično. Zbog njihovog lakog davanja tablete i kapsule predstavljaju najpovoljniji oblik oralne jedince doziranja, u kojem slučaju se očito upotrebljavaju kruti farmaceutski nosači. Za parenteralne sastave, nosač obično uključuje sterilnu vodu, barem velikim dijelom, iako se mogu uključiti i drugi sastojci, na primjer za potpomaganje topivosti. Mogu se pripraviti injekcijske otopine u kojima, na primjer, nosač uključuje otopinu soli, otopinu glukoze ili mješavinu otopine soli i glukoze. Injekcijske otopine koje sadrže spojeve formule (I) mogu se formulirati u ulju za produljeno djelovanje. Prikladna ulja u tu svrhu jesu, na primjer, kikirikijevo ulje, sezamovo ulje, ulje iz sjemeki pamuka, kukuruzno ulje, ulje iz sjemenki soje, sintetički glicerolni esteri s dugačkim lancem masnih kiselina i njihove mješavine, i druga ulja. Također se mogu proizvesti injekcijske suspenzije, u kojem slučaju se mogu upotrijebiti prikladni tekući nosači, sredstva za suspendiranje i slično. U sastavima prikladnim za perkutano davanje nosač prema potrebi uključuje sredstvo za pospješivanje prodiranja i/ili prikladno sredstvo za kvašenje, prema potrebi kombinirano s malim udjelima prikladnih dodataka bilo koje naravi, koji dodaci ne uzrokuju nikakve štetne efekte na koži. Spomenuti dodaci mogu olakšati davanje kroz kožu i/ili mogu pomoći kod pripravljanja željenih sastava. Ovi sastavi mogu se dati raznim putevima, npr. kao transdermalni flaster, kao oblog ili pomast. Adicijske soli spojeva (I), zbog njihove povišene topivosti u vodi u usporedbi s odgovarajućim slobodnim bazama ili slobodnim kiselim oblikom, su očigledno prikladnije za pripravljanje vodenih sastava.
Posebno korisno je formulirati gore spomenute farmaceutske sastave u obliku jediničnog doziranja za lakše davanje i ujednačenost doziranja. Jedinični oblik doziranja, kako se rabi ovdje u opisu i patentnim zahtjevima, odnosi se na fizički odvojene jedinice kao jedinične doze, pri čemu svaka jedinica sadrži prethodno određenu količinu aktivnog sastojka izračunatog tako da proizvede željeni terapeutski učinak, zajedno sa željenim farmaceutskim nosačem. Primjeri takovih jediničnih oblika doziranja jesu tablete (uključiv zarezane ili prevučene tablete), kapsule, pilule, paketiće praška, hostije, injekcijske otopine ili suspenzije, čajne žličice, jušne žlice i slično, i njihova odvojene višestruka pakiranja.
Slijedeći primjeri su predviđeni za ilustraciju predloženog izuma.
Eksperimentalni dio
Primjer A.1
Mješavinu dimetil(tetrahidro-3,3-difenil-2-furiliden)-amonijevog bromida (0,01 mol), proizvedenog kako je opisano u US 3,714,159, (±)-4-(11,12-dihidro-6H-benzamidazo[2,1-b]-[3]benzazepin-6-il)piperidina (0,01 mol), Na2CO3 (0,01 mol) i KJ (10 mg) u metil izobutil ketonu (200 ml) miješa se i refluktira preko noći. Otapalo se ispari i ostatak se preuzme u vodu/CH2Cl2. Organski sloj se odvoji i vodeni sloj se ekstrahira ponovno sa CH2Cl2. Sjedinjeni organski slojevi se osuše, profiltriraju i otapalo se ispari. Ostatak se očisti na staklenom filteru preko silika gela (sredstvo za ispiranje: CH2Cl2/CH3OH 95/5 do 90/10). Čiste frakcije se skupe i ispare. Ostatak kristalizira iz CH3CN, čime se dobije 0,88 g (15%) (±) -4-(11,12-dihidro-6H-benzamid-azo[2,1-b][3]benzazepin-6-il)-N,N-dimetil-α,α-difenil-1-piperidinbutanamida (spoj 1; talište 255,3°C).
Primjer A.2
K mješavini 4-(3-brom-2-oksopropil)-N,N-dimetil-α,α-difenil-1-piperidinbutanamid monohidrobromida (13 g) u metanolu (80 ml) uz miješanje i pri 70°C doda se (2,6-dimetilfenil)tioureu (4,1 g). Miješanje se nastavi još 1 sat pri temperaturi refluksa. Otapalo se ispari i ostatak se preuzme u vodu. Doda se toliko kalijevog karbonata da se dobije pH pribl. 9 i mješavinu se ekstrahira s etil acetatom. Organsku fazu se očisti kiselo bazičnom ekstrakcijom, osuši, profiltrira i otapalo se ispari. Ostatak kristalizira iz metanola. Talog se odfiltrira, ispere i osuši, čime se dobije 6,7 g (52%) 4-[[2-[[2,6-(dimetilfenil)amino]-4-tiazolil]metil]-N,N-dimetil-α,α-difenil-1-piperidinbutanamida (spoj 47; talište 210,5°C).
Na analogni način su proizvedeni:
4-[[2-[[2,6-(diklorfenil)amino]-4-tiazolil]metil]-N,N-dimetil-α,α-difenil-1-piperidinbutanamid (spoj 48; talište 207,0°C);
N,N-dimetil-4-[[2-(metilamino)-4-tiazoliljmetil]-α,α-difenil-1-piperidinbutanamida (spoj 49; talište 188,3°C).
Primjer A.3
K mješavini NaH (78%-tna disperzija; 0,55 g) u 1,4-dioksanu (50 ml) uz miješanje se doda 1-(4-fluorfenil)-N,N-dimetil-4-okso-α,α-difenil-1,3,8-triazaspiro[4,5]dekan-8-butanamid (7,7 g). Nakon miješanja 1 sat pri sobnoj temperaturi, smjesu se zagrije na 60°C i doda se (klor-metil)benzen (2,3 g). Miješanje se nastavi preko noći pri 60°C, reakcijsku smjesu se prelije na vodu i smjesu se ekstrahira sa CHCl3. Ekstrakt se ispere s vodom, osuši, profiltrira i otapalo se ispari. Ostatak se očisti kromatografijom na stupcu preko silika gela upotrebom CHCl3 i 3%-tnog metanola, zasićenog s plinovitim amonijakom, za ispiranje. Čiste frakcije se skupe i otapalo se ispari. Ostatak se triturira u n-heksanu. Talog se odfiltrira i osuši, čime se dobije 2 g 1-(4-fluorfenil)-N,N-dimetil-4-okso-α,α-difenil-1-fenilmetil-1,3,8-triazaspiro[4,5]dekan-8-butanamida (spoj 50; talište 139,8°C).
U tablicama 1 i 2 navedeni su spojevi koji su proizvedeni u skladu s primjerom A.1. Neki spojevi su proizvedeni upotrebom drugačije baze i/ili otapala u odnosu na one upotrijebljene u primjeru A.1. Također, neki spojevi su proizvedeni bez upotrebe KJ. Uvjeti reakcija su navedeni u stupcu "uvjeti reakcije" u tablicama 1 i 2. U spomenutom stupcu MIK znači metilizobutil keton, DMA je N,N-dimetil-acetamid i DMF znači N,N-diemtilformamid.
Tablica 1
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U skladu s primjerom 1, ali bez upotrebe KJ proizveden je 1-(5-klor-2-metilfenil)-N,N-dimetil-4-okso-α,α-difenil-1,3,8-triazaspiro[4,5]dekan-8-butanamid (spoj 46; talište 175, 7°C).
Farmakološki primjer
Primjer B.1
Pokus transporta preko GlyT1 transportera
Subkonfluentne HEK 293-GlyT1 stanice (tj. stanična linija koja stabilno umnaža humani transporter 1 glicina) zasađene su u Cytostar T pločice pri koncentraciji od 50.000 stanica po jamici u 100 µl DMEM medija (Dulbeccov modificirani Eagle medij nadopunjen s 10% fetalnog goveđeg seruma, 1 mM Na-piruvatom, 2 mM glutaminom, 100 U penicilina/ml i 0,1 mg/ml streptomicina). Stanice su inkubirane 48 sati pri 37°C, 5% CO2 i 95% vlage.
Na dan 3, stanice su isprane upotrebom Tecan PW96 uređaja za ispiranje, kontroliranog pomoću mikroprocesora, konstruiranog za ispiranje svih 96 jamica mikrotitarske ploče istovremeno s uzimanjem pufera (25 mM Hepes, 5,4 mM K-glukonat, 1,8 mM Ca-glukonat, 0,8 mM MgSO4, 140 mM NaCl, 5 mM glukoza, 5 mM alanin, podešeno na pH 7,5 s 2M Tris). Tecan PW 96 je bio programiran tako da ispere stanice pet puta ostavljajući 75 µl u svakoj jamici. Ispitni spojevi su otopljeni u DMSO u različitim koncentracijama u mikromolarnom području. 1 µl otopine dodano je u svaku jamicu i stanice su inkubirane 5' do 10' pri sobnoj temperaturi. Dodano je 25 µl 30 µM [U14C] glicina razrijeđenog u protočnom puferu. Stanice su inkubirane 1 sat pri sobnoj temperaturi. Pločice su zatim začepljene i pokupljeni uzeti [U14C] glicin je utvrđen na Packardovoj mikrotitarskoj pločici scintilacijskog brojača (TopCount). Iz rezultata dobivenih za različite koncentracije, za svaki ispitani lijek izračunata je koncentracija koja daje 50%-tnu inhibicijz (IC50) ponovnog uzimanja glicina. Izračunati podaci za ispitne spojeve prema izumu prikazani su u tablici 3 kao vrijednosti pIC50 (vrijednosti negativnog logaritna za IC50).
C. Primjeri sastava
Slijedeća formulacija je primjer tipičnog farmaceutskog sastava prikladnog za sistemsko davanje životinjama i ljudima u skladu s predloženim izumom. "Aktivan sastojak" (A.I.) odnosi se na spoj formule (I) ili na njegovu farmaceutski prihvatljivu adicijsku sol.
Primjer C.1: tablete prevučene filmom
Pripravaljanje jezgre tablete:
Mješavinu od 100 g A.I., 570 g laktoze i 200 g škroba dobro se promiješa i zatim se navlaži s otopinom od 5 g natrijevog dodecil sulfata i 10 g polivinilpirolidona u pribl. 200 ml vode. Vlažnu praškastu smjesu se prosije, osuši i ponovno prosije. Zatim se doda 100 g mikrokristalinične celuloze i 15 g hidrogeniranog biljnog ulja. Sve zajedno se dobro promiješa i ispreša u tablete, pri čemu se dobije 10.000 tableta od kojih svaka sadrži 10 mg aktivnog sastojka.
Prevlaka
K otopini od 10 g metil celuloze u 75 ml denaturiranog etanola doda se otopinu od 5 g etil celuloze u 150 ml diklormetana. Zatim se doda 75 ml dikloretana i 2,5 ml 1,2,3-propantriola. 10 g polietilen glikola se rastali i otopi u 75 ml diklormetana. Potonju otopinu se doda k prethodnoj i zatim se doda 2,5 mg magnezijevog oktadekanoata, 5 g polivnilpirolidona i 30 ml koncentrirane suspenzije boje i sve se homogenizira. Jezgre tableta se prevuku s tako dobivenom smjesom u uređaju za prevlačenje tableta.
Ispitani su također spoj 51, koji je bio 4-[[1-[(4-fluorfenil)metil]-1H-benzimidazol-2-il]-N,N-dimetil-α,α-difenil-1-piperidinbutanamid, kako je opisan u US-4,695,575, i spoj 52, koji je bio 4-[[9-[(4-metoksifenil)-metil]-9H-purin-8-il]amino]-N,N-dimetil-α,α-difenil-1-piperidinbutanamid (E)-2-butendioat (2:5), kako je opisan u US-5,008,268.
Tablica 3
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Claims (10)

1. Upotreba spoja koji inhibira transport glicina za proizvodnju lijeka za liječenje poremećaja središnjeg i perifernog živčanog sistema, pri čemu spomenuti spoj ima formulu [image] njegovog N-oksida, stereokemijski izomernog oblika ili njegove farmaceutski prihvatljive adicijske soli, naznačena time, da svaki od R1 i R2 neovisno predstavlja vodik ili C1-4-alkil; X je radikal formule [image] u kojoj crtkana linija predstavlja proizvoljnu vezu; [image] R3 predstavlja radikal formule [image] u kojoj svaki od R6 i R7 neovisno predstavlja vodik ili se obadva mogu uzeti zajedno s ugljikovim atomima na koje su vezani tako da se dobije fenilni prsten; R8 predstavlja vodik ili halogen; n je 1 ili 2; R4 predstavlja vodik, hidroksi, C1-4-alkiloksi, C1-4-alkiloksi-C1-4-alkil ili C1-4-alkiloksi; R5 predstavlja diarilmetiloksi-C1-4-alkil ili radikal formule [image] u kojoj B1 predstavlja -CH2, -CH(OH)-, -NH-, -CH2-NH- ili izravnu vezu; B2 predstavlja -NH-, -CH2 ili izravnu vezu; B3 predstavlja -NR12 -, -CH2-, -C(=O) ili izravnu vezu; B7 predstavlja -C1-4-alkandiil-NH- ili -NH-C1-4-alkil; B8 predstavlja -NR19-, -CH2- ili -CH(aril)-; svaki Y neovisno predstavlja O ili S; -a1=a2-a3=a4- predstavlja dvovalentni radikal formule -CH=CH-CH=CH- (b-1-a) ili -NH=CH-N=CH- (b-1-b); u kojoj vodikov atom u radikalu (b-1-a) može biti zamijenjen s hidroksi; R9 predstavlja C1-4-alkil; ili C1-4-alkil supstituiran s arilom, tienilom, furanilom, furanil supstituiran s hidroksi-C1-4-alkilom, ili tiazolil; R10 predstavlja aril, arilamino, C1-4-alkilamino, C1-4-alkiltio; R11 predstavlja vodik, C1-4-alkil, halogen ili trifluor-metil; R12 predstavlja vodik ili C1-4-alkilkarbonil; R13 predstavlja vodik, C1-4-alkil ili aril; R14 predstavlja vodik ili halogen; svaki od R15 i R16 neovisno predstavlja vodik ili aril; R17 predstavlja vodik ili C1-4-alkil; R18 predstavlja aril, 10,11-dihidro-5H-dibenzo[b,f]-azepin-5-il ili C1-4-alkil prema potrebi supstituiran s jednim ili dva supstituenta od kojih je svaki neovisno odabran između C3-7-cikloalkila ili arila; R19 predstavlja vodik, C1-4-alkilkarbonil ili diaril-C1-4-alkil; svaki od R20, R21, R22 i R23 neovisno predstavlja vodik, C1-4-alkil ili aril; R24 predstavlja vodik ili trifluormetil; R25 predstavlja vodik ili halogen; i u slučaju da R5 predstavlja radikal formule (b-3), tada R4 također može biti fenil-C1-4-alkilaminokarbonil; i R4 i R5 se mogu uzeti zajedno tako da tvore spiro radikal formule [image] u kojoj svaki od R26 i R27 neovisno predstavlja vodik, C1-4-alkil, aril ili aril-C1-4-alkil; aril predstavlja fenil, ili fenil supstituiran s 1 ili 2 supstituenta neovisno odabrana između C1-4-alkila, halogenog, trifluormetila, hidroksi i C1-4-alkoksi.
2. Upotreba prema zahtjevu 1, naznačena time, da R1 i R2 predstavljaju metil.
3. Upotreba prema zahtjevu 1 ili 2, naznačena time, da X predstavlja radikal formule (a) ili (b).
4. Upotreba prema zahtjevu 1, naznačena time, da je poremećaj psihoza, bol, epilepsija, neurodegenerativna bolest, kap, trauma glave ili multipla skleroza.
5. Spoj formule (I) kako je definiran u bilo kojem zahtjevu od 1 do 3, naznačen time, da pod uvjetom kad R4 predstavlja vodik i R5 je radikal formule (b-1), u kojoj B1 predstavlja -CH2- i R9 je 4-fluorbenzil, tada je -al=a2-a3=a4- različit od -CH=CH-CH=CH-; i ako R4 predstavlja vodik i R5 je radikal formule (b-1), u kojoj B1 predstavlja -NH- i R9 je 4-metoksibenzil, tada je -a1=a2-a3=a4 - različit od -CH=N-CH=CH-.
6. Spoj prema zahtjevu 5, naznačen time, da R5 predstavlja diarilmetiloksi-C1-4-alkil ili radikal formule (b-2), (b-3), (b-4), (b-5), (b-6), (b-7), (b-8), (b-9), (b-10), (b-11), (b-12) ili (b-13); ili R5 se može uzeti zajedno s R4 tako da tvore spiro radikal formule (b-14).
7. Farmaceutski sastav, naznačen time, da sadrži farmaceutski prihvatljiv nosač i, kao aktivan sastojak, terapeutski učinkovitu količinu spoja opisanog u zahtjevu 5 ili 6.
8. Postupak za proizvodnju farmaceutskog sastava prema zahtjevu 7, naznačen time, da se terapeutski učinkovitu količinu spoja opisanog u zahtjevu 5 ili 6 temeljito pomiješa s farmaceutskim nosačem.
9. Spoj prema zahtjevu 5 ili 6, naznačen time, da se upotrebljava kao lijek.
10. Postupak za proizvodnju spoja opisanog u zahtjevu 5, naznačen time, da intermedijat formule (II), u kojoj W predstavlja odgovarajući suprotni ion ili njegov funkcionalni derivat, reagira s intermedijatom formule (III) u reakcijski inertnom otapalu, u prisutnosti prikladne baze, i prema potrebi u prisutnosti kalijevog jodida; [image] i, po želji, spoj formule (I) prevede se u kiselinsku adicijsku sol obradom s kiselinom, ili se prevede u bazičnu adicijsku sol obradom s bazom, ili obrnuto, kiselu adicijsku sol prevede se u slobodnu bazu obradom s lužinom, ili se bazičnu adicijsku sol pretvori u slobodnu kiselinu obradom s kiselinom; i, po želji, proizvede se njegov N-oksid i/ili njegov stereokemijski izomerni oblik.
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