NO310234B1 - Fremgangsmåte for fremstilling av corticotropin- frigjöringsfaktorantagonister - Google Patents
Fremgangsmåte for fremstilling av corticotropin- frigjöringsfaktorantagonister Download PDFInfo
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- NO310234B1 NO310234B1 NO20002391A NO20002391A NO310234B1 NO 310234 B1 NO310234 B1 NO 310234B1 NO 20002391 A NO20002391 A NO 20002391A NO 20002391 A NO20002391 A NO 20002391A NO 310234 B1 NO310234 B1 NO 310234B1
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- Prior art keywords
- alkyl
- cyano
- chlorine
- methyl
- fluorine
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Abstract
Corticotropin-fiigjørende faktor (CRF) antagonister med formel IV, hvor definisjonene er som angitt i beskrivelsen, er beskrevet Disse forbindelsene og deres farmasøytisk akseptable salter kan anvendes ved behandling av CNS og stress-relaterte sykdommer og lidelser.
Description
Den foreliggende oppfinnelse angår fremgangsmåte for fremstilling av corticotropin-frigjøringsfaktorantagonister. Disse kan anvendes for behandling av visse lidelser i det sentrale nervesystem (CNS) og andre lidelser.
CRF antagonister er nevnt i US patentene 4605642 og 5063245 hvor man refererer til peptider og pyrazolinoner henholdsvis. Betydningen av CRF antagonister er angitt mange steder i litteraturen, for eksempel som angitt i US patent 5063245 som her inngår som en referanse. En nylig utgitt oversikt med hensyn til de forskjellige aktivitetene til CRF antagonister kan finnes i M. J. Owens et al Pharm. Rev. Vol.43 sidene 425 til 473 (1991) som også inngår her som en referanse. Basert på undersøkelser som er beskrevet i disse to og andre referanser, er det vist at CRF antagonister meget effektivt kan brukes ved behandlingen av en rekke stressrelaterte sykdommer som depresjon, nervøsitet, hodepine, irritasjoner i tarm-systemet, inflammatoriske sykdommer, undertrykking av immunsystemet, Alzheimers sykdom, sykdommer knyttet til magesekken, anorexia nervosa, blødningsstress, abstinenssymptomer i forbindelse med alkohol og medikamenter, medikament- og narkotikaavhengighet, sterilitet, hodepine, slag, og stressinduserte infeksjoner både hos mennesker og dyr.
Foreliggende oppfinnelse vedrører følgelig fremgangsmåte for fremstilling av en forbindelse med formelen
hvor
Ri9 er metyl eller etyl;
D er klor;
Aer-CR7ellerN;
Z er NH, O, S, -N(Ci-C2 alkyl) eller -C(Ri3Ri4), hvor Rn og Rh hver er uavhengig av hverandre hydrogen, trifluormetyl eller metyl, eller hvor en av Ru og RH er cyano mens den andre er hydrogen eller metyl;
R4 er hydrogen, C1-C4 alkyl, fluor, klor, brom, iod, C|-C4alkoksy, trifluorrnetoksy, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2OF3, CF3, amino, nitro, -NH(C,-C4 alkyl), -N(CH3), -NHCOCH3, -NHCONHCH3, -SOn(C,-C4 alkyl), hvor n er 0,1 eller 2, cyano, hydroksy, -CO(CrC4 alkyl), -CHO, cyano eller -COO(CrC4 alkyl) hvor nevnte C,-C4 alkyl-gruppe eventuelt kan inneholde en dobbelt- eller trippelbinding og eventuelt kan være substituert med en substituent valgt fra hydroksy, amino, -NHCOCH3, -NH(Ci-C2 alkyl),
-N(C,-C2 alkyl)2, -COO(Ci-C4 alkyl), -CO(d-C4 alkyl), CrC3 alkoksy, CrC3 tioalkyl, fluor, klor, cyano og nitro; og
R5 er fenyl eller pyridyl, og R5 er substituert med fra en til tre substituenter uavhengig av hverandre valgt fra fluor, klor, CrC6 alkyl og Ci-C6 alkoksy, eller med en substituent valgt fra hydroksy, iod, brom, formyl, cyano, nitro, trifluormetyl, amino, -(Ci-Cé alkyl)0(Ci-C6)-alkyl, -NHCH3, -N(CH3)2, -COOH, -COO(CrC4 alkyl), -CO(C,-C4 alkyl), -S02NH(d-C4-alkyl), -S02N(C,-C4 alkyl)(Ci-C2 alkyl), -S02NH2, -NHS02(Cj-C4 alkyl), -S(C,-C6 alkyl) og
-S02(Ci-C6 alkyl), hvor nevnte Ci-C4 alkyl og Ci-C6 alkylgrupper i de forannevnte R5 grupper eventuelt kan være substituert med en eller to fluorgrupper eller med en substituent valgt fra hydroksy, amino, metyl-amino, dimetylamino og acetyl; kjennetegnet ved en forbindelse med formelen
hvor Ri 9, R4 og R5 er som definert ovenfor, og R7 er hydrogen, metyl, fluor, klor, brom, iod, cyano, hydroksy, -0(C,-C4 alkyl), -C(0)(C,-C4 alkyl), -C(0)0(CrC4 alkyl), -OCF3, CF3,
-CH2OH, -CH2OCH3 eller -CH2OCH2CH3, omsettes med fosfortriklorid.
Produktet som fremstilles ifølge foreliggende oppfinnelse kan anvendes som et farmasøytisk preparat for behandling av (a) en lidelse eller sykdom hvor behandlingen kan utføres eller lettes ved å antagonisere CRF, og som innbefatter lidelser som er indusert eller lettet ved hjelp av CRF, eller (b) en lidelse eller sykdom valgt fra gruppen bestående av inflammatoriske sykdommer som revmatisk arthritis og osteoarthritis, smerte, astma, psoriasis og allergi; generelle nervøsitetssykdommer; panikk, fobi, tvangsforestillinger, posttraumatiske stress-sykdommer, søvnproblemer som er indusert eller utløst på grunn av stress, smerte-oppfatningssykdommer som fibromyalgi, sinnslidelser som depresjon, og her inngår større depresjoner, enkeltdepresjoner, tilbakevendingsdepresjoner, depresjoner som er utløst ved barnemishandling og postparturndepresjoner, dystemi, bipolare sykdommer, cyklotymi, trett-hetssyndromer; stressindusert hodepine, kreft, sykdommer som skyldes irritasjon i tarmkanalen, Crohns sykdom, spastisk kolon, humant immunsviktvirus (HIV) infeksjoner, neuro-degenererende sykdommer som Alzheimers sykdom, Parkinsons sykdom og Huntingtons sykdom; sykdommer i tarmkanalen; spiseforstyrrelser som anoreksia og bulimi nervosa; blødningsstress, kjemisk avhengighet og tilvenning (for eksempel avhengighet med hensyn til alkohol, kokain, heroin, benzodiazepiner og andre medikamenter), abstinenssymptomer i forbindelse med medikamenter og alkohol; stressinduserte psykotiske episoder; det eutyroide sykdomssyndrom; syndromer i forbindelse med manglende antidiaretisk hormon (ADH), overvekt; sterilitet; hodetraumer; ryggmargstraumer; ischemiske nerveskader (for eksempel cerebral ischemi som cerebral hippokampal ischemi); eksitoksiske nerveskader; epilepsi, slag, sviktende immunsystem, og her inngår stressindusert immunsvekkelse (for eksempel stress hos svin, transportfeber hos storfe, paroksymal fibrilering hos hester og funksjonssvikt som er indusert i burhøns, stress som oppstår under klipping av sauer eller stress som oppstår hos hunder som et resultat av forholdet mellom menneske og dyr); muskelkramper, urinveis-inkontinens, senilitet av Alzheimertypen; multiinfarktdemensia; amyotrofisk lateral sklerose; og hypoglykemi hos pattedyr, og her inngår mennesker.
Fremgangsmåte for fremstilling av forbindelsene er beskrevet i det etterfølgende.
I diskusjonen og i reaksjonsskjemaene som vil bli beskrevet i det etterfølgende, er R4, R5, R19, A, D og de stiplede linjene og strukturformen IV, hvis intet annet er angitt, som definert ovenfor.
Med hensyn til definisjonen av C1-C6 alkylgruppene, så er disse rette eller grenete alkylgrupper med fra et til seks karbonatomer, for eksempel metyl, etyl, isopropyl, t-butyl eller heksyl.
Når R5 er en hetrocyklisk gruppe, så er gruppen festet via et karbonatom.
Med hensyn til halogen, så innbefatter dette fluor, klor, brom eller iod hvis intet annet er angitt.
Forbindelser med formel IV hvor D er klor og ZR5 er NHR5, kan fremstilles fra forbindelse med formel V:
hvor A og R4 er som definert med referanse til formel I, og Ri 9 er som definert ovenfor, ved en reaksjon med R5NH2. Reaksjonen bør skje i tetrahydrofuran eller dimetylsulfoksyd ved temperaturer mellom 0 og 150°C, fortrinnsvis 50 og 130°C. Forbindelsene med formel IV hvor D er klor og Z er O, S, kan fremstilles ved at man reagerer forbindelsen med formel V med R5OH, R5SH, R5NH2 eller R5CHR21. Reaksjonen bør skje i nærvær av en base som er i stand til å deprotonere R5ZH, for eksempel natrium hydrid, kalium hydrid, kalium karbonat, litium eller natrium bis(trimetylsilyl)amid, litium eller natrium dialkylamid, natrium eller kalium (C1-C4 alkoksyd) eller n-butyllitium, med eller uten andre organometall halogenider som kobber (I) bromid, iodid eller klorid, kobber (II) oksyd, kobber (I) oksyd, kobber metall og trialkyltinklorid. Eksempler på løsemidler som kan brukes er tetrahydrofuran, dimetylsulfoksyd, acetonitril, metylen klorid, l-metyl-2-pyrrolidinonj pyridin, kinolin, N,N-dialkyl-acetamider, 2,4,6-trimetylpyridin, N,N-dialkylformamider, for eksempel N,N-dimetyl-formamid (DMF), heksametyl fosforamid og toluen. Reaksjonstemperaturen kan variere fra 0 til 180°C, fortrinnsvis mellom 0 og 150°C.
Forbindelser med formel IV hvor A er CR7, D er klor og Z er O, S, kan fremstilles ved at man reduserer forbindelser med formel X som vist ovenfor, hvor R7 og Z er som definert ovenfor, med et reduksjonsmiddel som fosfor triklorid i et passende løsemiddel som metylen klorid eller kloroform, ved temperaturer mellom 0 og 100°C, fortrinnsvis mellom romtemperatur og kokepunktet for løsemidlet.
Forbindelser med formel X kan fremstilles fra forbindelser med formel XI som vist ovenfor, hvor R4 er som definert i formel I, og Ri 9 er som definert ovenfor (for eksempel metyl eller etyl), ved en reaksjon med en forbindelse med formel R5OH, R5SH eller R5CHR21. Denne reaksjonen skjer i nærvær av en base som er i stand til å deprotonere R5ZH, f.eks. natrium hydrid, kalium hydrid, litium, natrium eller kalium bis(trimetylsilyl)amid, litium, natrium eller kalium dialkylamid, natrium eller kalium C]-C4alkoksyd eller n-butyl-litium. Egnede løsemidler innbefatter tetrahydrofuran, dioksan, dimetylsulfoksyd, l-metyl-2-pyrrolidinon, pyridin, N,N-di-(Ci-C4 alkyl)acetamider, acetamid, N,N-di-(Ci-C4 alkyl)-formamider, acetonitril, metylen klorid, touluen og xylen. Egnede reaksjonstemperaturer ligger mellom -78 og 150°C, fortrinnsvis mellom -40 og 150°C.
Forbindelser med formel IV hvor D er klor og Z er -N(Ci-C4 alky) kan fremstilles ved at man reagerer de tilsvarende forbindelser hvor Z er NH med en base ved temperaturer mellom -78 og 100°C, fortrinnsvis mellom 0°C og romtemperatur, hvoretter reaksjonen stoppes med C1-C4 alkyl iodid eller bromid. Egnede baser innbefatter for eksempel natrium hydrid, litium eller natrium bis(trimetylsilyl)amid, litium eller natrium dialkylamid eller n-butyllitium. Egnede løsemidler innbefatter for eksempel tetrahyrofuran, dimetylsulfoksyd, toluen, benzen eller metylenklorid.
De aktive forbindelser som fremstilles ifølge foreliggende oppfinnelse kan tilføres alene eller sammen med farmasøytisk akseptable bærestoffer og fortynningsmidler, enten i enkle eller mutiple doser. Egnede farmasøytiske fortynningsmidler eller bærestoffer innbefatter inerte faste fortynningsmidler eller fyllstoffer, sterile vandige løsninger eller forskjellige organiske løsemidler. De farmasøytiske preparater som kan fremstilles, kan lett tilføres på en rekke forskjellige doseringsformer som tabletter, pulver, drops, siruper, injiserbare løsninger og lignende. Slike farmasøytiske preparater kan, hvis det er ønskelig, inneholde andre ingre-dienser eller bestanddeler som smaksstoffer, bindemidler, fortynningsmidler og lignende. For en oral bruk kan man for eksempel fremstille tabletter med forskjellige fortynningsmidler som natriumsitrat, kalsiumkarbonat og kalsiumfosfat sammen med forskjellige nedbrytningsmidler som stivelse, metylcellulose, algininsyre og visse komplekse silikater sammen med bindemidler som polyvinylpyrrolidinon, sukrose, gelatin og akacia. Videre kan man ofte bruke smøremidler som magnesium stearat, natrium laurylsulfat og talkum i slike tabletter. Faste preparater av en lignende type kan også anvendes som fyllstoffer i myke og harde gelantin-kapsler. Foretrukne stoffer for dette formål innbefatter laktose eller melkesukker og høymole-kylære polyetylen glykoler. Når vandige suspensjoner eller safter eller løsninger er ønskelige for oral bruk, så kan den aktive bestanddelen kombineres med forskjellige søtnings- og smaksstoffer, fargestoffer og pigmenter hvis dette er ønskelig, videre emulgerings- eller suspende-ringsmidler sammen med fortynningsmidler som vann, etanol, propylen glykol, glycerin og kombinasjoner av disse.
For parenteralt bruk kan man anvende løsninger som inneholder en aktiv forbindelse fremstilt ifølge foreliggende oppfinnelse eller et farmasøytisk akseptabelt salt av denne i sesamolje eller jordnøttolje, vandig propylen glykol eller i sterile vanndige løsninger. Slike vanndige løsninger bør egnet buffres, hvis dette er nødvendig, og det flytende fortynnings-midlet må først gjøres isotonisk med tilstrekkelig saltløsning eller glukose. Disse spesielle vanndige løsningene er spesielt godt egnet for intravenøs, intramuskulær, subkutan og intra-peritoneal bruk. De sterile vanndige media som brukes er alle lett å fremstille ved hjelp av standardteknikk.
De effektive doser av forbindelsene som fremstilles vil avhenge av tilførselsvei og faktorer son. uardentens alder, vekt og tilstand, og vil vanligvis lett kunne bestemmes av legen. Dos? nrjgen vil også i høy grad være avhengig av den spesielle sykdom som behandles. For eksempel vil vanlige doser for stressinduserte sykdommer, inflammatoriske sykdommer, Alzheimers sykdom, gastro-intestinale sykdommer, anoreksia nervosa, blødende stress og medikament- og alkoholabstinenssymptomer vanligvis ligge i området fra 0,1 til 50 mg per kg kroppsvekt for den pasient som skal behandles.
Fremgangsmåter som kan brukes for å bestemme CRF antagonist aktiviteten for de foreliggende forbindelser og deres farmasøytisk akseptable salter, er beskrevet i Endocrinology, 116,1653-1659 (1985) ogPeptides, 10, 179-188 (1985).
Den foreliggende oppfinnelsen er illustrert ved hjelp av følgende fremstilling. Smelte-unktet er ukorrigert. Proton kjernemagnetisk resonans spektra (<!>H NMR) og C<13> kjernemagne-iske resonans spektra (C<13> NMR) ble målt for løsninger i deutero-kloroform (CDCI3), og topp posisjonene er angitt som deler per million (ppm) nedenfor tetrametylsilan (TMS). Formen på toppen er angitt som følger: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, bred.
FREMSTILLING A
4-KIor-3,6-dimetyl-2-(2,4,6-trimetyl-fenoksy)-pyridin
En løsning av 2,4,6-trimetlfenol (450 mg, 3,31 mmol) i 2 ml DMSO ble behandlet med 160 mg NaH (60% i olje, 4,5 mmol). Etter fem minutter tilsatte man 2,4-Diklor-3,6-di-metylpyridin (528 mg, 3 mmol). Blandingen ble holdt på et oljebad på 130°C i seks timer. Blandingen ble så tilsatt vann og ekstrahert med etyl acetat, og det organiske laget ble tørket og konsentrert til 812,5 mg av et råprodukt av to regioisomerer. Etter silika gel kolonne kromatografi hvor man brukte en 1:1 blanding av kloroform og heksan som elueringsmiddel, ble tittelforbindelsen isolert som 141 mg hvite krystaller, smeltepunkt 57-62°C; høy MS for Ci6H18CINO: beregnet 275,1072, funnet 275,70172; IR(KBr) 2951, 2920,1592, 1564 cm-1; <!>H NMR (CDC13) 5 6,87 (s, 2H), 6,77 (s,lH), 2,39 (s, 3H), 2,29 (s, 3H), 2,18 (s, 3H), 2,03 (s, 6H) ppm. Regiokjemien ble bestemt ved røntgenstrukturell analyse av den uønskede regio-isomeren 2-klor-3,6-dimetyl-4-(2,4,6-trimetyl-fenoksy)pyridin.
En løsning av 4-klor-2,5-dimetyl-6-(2,4,6-trimetyl-fenoksy)-pyridin 1-oksyd (34 mg) i 1 ml tørr metylen klorid ble tilsatt 2M PCI5 i metylen klorid (0,022 ml). Etter tilsetningen ble blandingen kokt under tilbakeløp i en halv time, avkjølt og konsentrert til tørrhet. Resten ble helt over i isvann og ekstrahert med metylen klorid, det organiske lag ble vasket med salt-løsning, nøytralisert med mettet natrium karbonat, tørket og konsentrert til 47 mg råprodukt. Dette ble utkrystallisert ved henstand og ga 31 mg (95%) av hvite krystaller av tittel-forbindelse.
Claims (1)
- Fremgangsmåte for fremstilling av en forbindelse med formelen hvorRi9 er metyl eller etyl;D er klor;Aer-CR7ellerN;Z er NH, O, S, -N(Ci-C2 alkyl) eller -C(Ri3Ri4), hvor R]3 og Ru hver er uavhengig av hverandre hydrogen, trifluormetyl eller metyl, eller hvor en av Rn og Ri4 er cyano mens den andre er hydrogen eller metyl;R4 er hydrogen, Ci-C4 alkyl, fluor, klor, brom, iod, Ci-C4 alkoksy, trifluormetoksy, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2OF3, CF3, amino, nitro, -NH(Ci-C4 alkyl), -N(CH3), -NHCOCH3, -NHCONHCH3, -SOn(C,-C4 alkyl), hvor n er 0, 1 eller 2, cyano, hydroksy, -CO(d-C4 alkyl), -CHO, cyano eller -COO(CrC4 alkyl) hvor nevnte CrC4 alkyl-gruppe eventuelt kan inneholde en dobbelt- eller trippelbinding og eventuelt kan være substituert med en substituent valgt fra hydroksy, amino, -NHCOCH3, -NH(Ci-C2 alkyl), -N(C,-C2 alkyl>2, -COO(Ci-C4 alkyl), -CO(C,-C4 alkyl), C,-C3 alkoksy, CrC3 tioalkyl, fluor, klor, cyano og nitro; ogR5 er fenyl eller pyridyl, og R5 er substituert med fra en til tre substituenter uavhengig av hverandre valgt fra fluor, klor, C1-C6 alkyl og C1-C6 alkoksy, eller med en substituent valgt fra hydroksy, iod, brom, formyl, cyano, nitro, trifluormetyl, amino, -(CpCé alkyl)0(Ci-C6)-alkyl, -NHCH3, -N(CH3)2, -COOH, -COO(C,-C4 alkyl), -CO(C,-C4 alkyl), -S02NH(CrC4-alkyl), -S02N(C,-C4 alkyl)(C,-C2 alkyl), -S02NH2, -NHSOz(C,-C4 alkyl), -S(C,-C6 alkyl) og -S02(Ci-C6 alkyl), hvor nevnte Cj-C4 alkyl og Ci-Cé alkylgrupper i de forannevnte R5 grupper eventuelt kan være substituert med en eller to fluorgrupper eller med en substituent valgt fra hydroksy, amino, metyl-amino, dimetylamino og acetyl;karakterisert ved at en forbindelse med formelenhvor Ri 9, R4 og R5 er som definert ovenfor, og R7 er hydrogen, metyl, fluor, klor, brom, iod, cyano, hydroksy, -0(Ci-C4 alkyl), -C(0)(d-C4 alkyl), -C(0)0(C,-C4 alkyl), -OCF3, CF3, -CH2OH, -CH2OCH3 eller -CH2OCH2CH3, omsettes med fosfortriklorid.
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US25551494A | 1994-06-08 | 1994-06-08 | |
PCT/IB1995/000439 WO1995033750A1 (en) | 1994-06-08 | 1995-06-06 | Corticotropin releasing factor antagonists |
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NO20002391A NO310234B1 (no) | 1994-06-08 | 2000-05-08 | Fremgangsmåte for fremstilling av corticotropin- frigjöringsfaktorantagonister |
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