NO343371B1 - Nye forbindelser med DGAT1-aktivitet, farmasøytiske sammensetninger inneholdende slike og anvendelse derav - Google Patents
Nye forbindelser med DGAT1-aktivitet, farmasøytiske sammensetninger inneholdende slike og anvendelse derav Download PDFInfo
- Publication number
- NO343371B1 NO343371B1 NO20084490A NO20084490A NO343371B1 NO 343371 B1 NO343371 B1 NO 343371B1 NO 20084490 A NO20084490 A NO 20084490A NO 20084490 A NO20084490 A NO 20084490A NO 343371 B1 NO343371 B1 NO 343371B1
- Authority
- NO
- Norway
- Prior art keywords
- phenyl
- cyclohexyl
- acetic acid
- pyridin
- ylamino
- Prior art date
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
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- RCYGBTZMDNSHGT-UHFFFAOYSA-N methyl 2-[4-[4-[5-[[6-(trifluoromethyl)pyridin-3-yl]amino]pyridin-2-yl]phenyl]cyclohexyl]acetate Chemical compound C1CC(CC(=O)OC)CCC1C1=CC=C(C=2N=CC(NC=3C=NC(=CC=3)C(F)(F)F)=CC=2)C=C1 RCYGBTZMDNSHGT-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
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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
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- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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Abstract
Foreliggende oppfinnelse tilveiebringer organiske forbindelser med følgende struktur: A-L1-B-C-D-L2-E som er anvendelige for behandling eller hindring av tilstander eller forstyrrelser assosiert med DGAT1 -aktivitet hos dyr, særlig mennesker.
Description
Fedme kan ses på som en energibalanseforstyrrelse, som oppstår når energiinntak overskrider energiforbruk, hvor de fleste av overskuddskaloriene omdannes til triglyserider og lagres i adiposevev. Medisineringer pr. i dag godkjent for behandling av fedme forsøker å gjenopprette energibalansen primært ved å redusere energiinntak ved enten å undertrykke appetitt eller interferere med lipidabsorpsjon i tynntarmen. På grunn av den raske økningen i forekomst av fedme verden over og mangel på effektivitet ved verserende medisinske behandlinger, er nye farmakologiske behandlinger for fedme påkrevet.
En potensiell terapeutisk strategi involverer inhibering av triglyseridsyntese. Selv om triglyserider er essensielle for normal fysiologi, resulterer overdreven triglyseridakkumulering i fedme og, særlig når den forekommer i ikke-adiposevev, er assosiert med insulinresistens. DGAT er et enzym som katalyserer det siste trinnet i triacylglyserolbiosyntesen. DGAT katalyserer kobling av et 1,2-diacylglyserol med et fettacyl-CoA som resulterer i koenzym A og triacylglyserol. To enzymer som fremviser DGAT-aktivitet har blitt identifisert: DGAT1 (acyl coA-diacylglyserol acyltransferase 1, se Cases et al. Proc. Natl. Acad. Sci.95:13018-13023, 1998) og DGAT2 (acyl coA-diacylglyserol acyltransferase 2, se Cases et al., J. Biol. Chem.276:38870-38876, 2001). DGAT1 og DGAT2 deler ikke signifikant proteinsekvenshomologi. Viktig er at DGAT1-utslagsmus beskyttet fra høyfettdiettvektøkning og insulinresistens (Smith et al., Nature Genetics 25:87-90, 2000). Fenotypen til DGAT1-utslagsmusen viser at en DGAT1-inhibitor har anvendelse for behandling av fedme og fedmeassosierte komplikasjoner.
WO2006113919 beskriver arylalkylsyrederivater som har DGAT-inhiberende aktivitet. WO2006044775 beskriver bifenyl-4-yl-karbonylaminosyrederivater som har DGAT-inhiberende aktivitet.
WO2006134317 beskriver oksadiazolderivater som har DGAT-inhiberende aktivitet. WO2006082952 beskriver amidderivater som har DGAT-inhiberende aktivitet.
WO2006082010 beskriver forbindelser som har DGAT-inhiberende aktivitet.
WO 2006/019020 A1 og WO 2006/004200 A1 beskriver ureaderivater som har DGAT-inhiberende aktivitet.
WO 2005/044250 A1 beskriver sulfonamidforbindelser som har DGAT-inhiberende aktivitet.
WO 2005/013907 A2 beskriver pyrrolo[1,2-b]derivater som har DGAT-inhiberende aktivitet.
WO 2005/072740 A2 beskriver forbindelser som har DGAT-inhiberende aktivitet.
JP 2005/206492 A2 beskriver sulfonamidforbindelser som har DGAT-inhiberende aktivitet.
JP 2004/067635 A2 beskriver fosforsyrediestere som har DGAT-inhiberende aktivitet. US 2004/0224997 A1 beskriver arylalkylsyrederivater som har DGAT1-inhiberende aktivitet.
WO 2004/04775 A2 beskriver sammensmeltede bicykliske nitrogeninneholdende heterocykler som har DGAT-inhiberende aktivitet.
US 2005/0101660 A1 beskriver dibenzo-p-dioksanderivater som har DGAT-inhiberende aktivitet.
WP 0573696 A1 beskriver heterobiarylderivater med den generelle strukturen R<1>NH-X1-X2-X3-Y1-Y3-Y4-E som har aggregeringsinhiberende aktivitet.
US 2005/0143422 A1 angår biarylsulfonamider og deres anvendelse som metalloproteinaseinhibitorer.
WO 00/25780 angår aminforbindelser med den generelle strukturen X-N(R)-B-D og deres anvendelse som IMPDH-inhibitorer.
WO 01/42241 angår substituerte pyridazinforbindelser som har cytokininhiberende aktivitet.
WO 02/055484 A1 angår en forbindelse med den generelle formelen R<1>-X<1>-Y-X<2>-A-B-X<3>-N(-X<4>-R<2>)-Z-Ar, hvor A og B representerer 5- eller 6-leddede aromatiske ringer. Forbindelsen kan anvendes som en blodlipidundertrykker.
WO 02/085891 A1 angår 2,6-substituerte kromanderivater som er anvendelige ved behandling av β-3-adrenoreseptormedierte tilstander.
WO 02/11724 A2 angår farmasøytiske sammensetninger som innbefatter 2-pyridinaminr som kan anvendes for å forebygge iskemisk celledød.
WO 03/062215 A1 angår substituerte tia-/oksa-/pyrazoler for å inhibere aktiviteten til en eller flere proteinkinaser.
WO 2004/000788 A1 angår ureidosubstituerte anilinforbindelser som er anvendelige som serinproteaseinhibitorer.
WO 2004/032882 A2 angår oksazolderivater som er anvendelige ved behandling av sykdommer assosiert med ikke-passende proteinkinaseaktivitet.
WO 2004/041810 A1 angår nitrogeninnholdende heteroarylforbindelser som er anvendelige for behandling av proteinkinasemedierte forstyrrelser.
WO 2004/046133 A1 angår aminoheterocykler anvendelige som VR-1-antagonister for behandling av smerte.
WO 2004/089286 A2 angår nitrogeninneholdende heteroarylforbindelser som er anvendelige for behandling av forstyrrelser assosiert med abnormal tyrosinkinaseaktivitet.
WO 2004/110350 A2 angår forbindelser med den generelle strukturen (A)-LA-(B)-LB-(C)-LC-(D) hvor A, B, C og D representerer aryl/heteroarylbestanddeler. Forbindelsene er anvendelige for behandling av neurodegenerative sykdommer.
WO 2005/012295 A1 angår substituerte tiazolbenzoisotiazoldioksoderivater som er anvendelige for behandling av diabetes.
WO 2005/016862 A1 angår substituerte arylalkansyrederivater som har prostaglandinproduksjonsundertrykkende aktivitet.
WO 2005/085227 A1 angår pyridinforbindelser som er anvendelige som inhibitorer av PKB/AKT-kinaseaktivitet og ved behandling av kreft og artritt.
WO 2005/100344 A1 angår forbindelser som innbefatter substituerte pyridazin- og pyrimidinbestanddeler. Disse forbindelser er anvendelige for inhibering av aktiviteten til en serin/treoninproteinkinase.
WO 2005/116003 A2 angår substituerte oksazolobenzoisotiazoldioksidderivater som er anvendelige ved behandling av diabetes.
WO 98/46574 angår pyridazin- og ftalazinderivater som er anvendelige som antikonvulsanter.
WO 99/24404 angår substituerte pyridinforbindelser som anvendelige som antiinflammatoriske midler.
Foreliggende oppfinnelse tilveiebringer derivater som er anvendelige for behandling eller forebygging av tilstander eller forstyrrelser assosiert med DGAT1-aktivitet hos dyr, særlig mennesker.
Forbindelsen tilveiebragt ved foreliggende oppfinnelse har følgende struktur
hvori:
- B er valgt fra gruppen som består av pyridin, pyridazin, pyrazin og oksazol;
- -L1er -NH-;
- A er valgt fra fenyl, pyridin og benzoksazol, hvori bestanddelen A er usubstituert eller substituert med 1 til 2 substituenter uavhengig valgt fra klor, metyl, metoksy, trifluormetyl og cyano;
- -L2er –CH2-; og
- E er valgt fra gruppen som består av –COOH, -COOCH3og –COOCH2CH3.
Foreliggende oppfinnelse omfatter også forbindelsene med formel:
hvori bestanddelen -L2-E er ekvivalent med gruppene E’.
Med mindre annet er indikert, er forbindelsene tilveiebragt i formlene ovenfor ment å inkludere alle farmasøytisk akseptable salter, stereoisomerer, krystallinske former eller polymorfer derav.
Foreliggende oppfinnelse tilveiebringer også farmasøytiske sammensetninger som innbefatter forbindelsene som definert ovenfor og en farmasøytisk akseptabel bærer eller eksipient.
Foreliggende oppfinnelse tilveiebringer også forbindelsene og de farmasøytiske sammensetninger som definert ovenfor for behandling eller forebygging av tilstander eller forstyrrelser assosiert med DGAT1-aktivitet hos dyr, særlig mennesker.
Foretrukket er forstyrrelsen valgt fra følgende: metabolittiske forstyrrelser slike som fedme, diabetes, anorexia nervosa, bulimi, kakeksi, syndrom X, insulinresistens, hypoglykemi, hyperglykemi, hyperuricemi, hyperisulinemi, hyperkolesterolemi, hyperlipidemi, dyslipedemi, blandet dyslipedimi, hypertriglyseridemi og ikkealkoholfettleversykdom; kardiovaskulære sykdommer, slike som aterosklerose, arteriosklerose, akutt hjertesvikt, kongestiv hjertesvikt, koronar arteriesykdom, kardiomyopati, myokardisk infarkt, angina pektoris, hypertensjon, hypotensjon, slag, iskemi, iskemisk reperfusjonsskade, aneurisme, restenose og vaskulær stenose; neoplastiske sykdommer, slik som faste tumorer, hudkreft, melanom, lymfom og endotelkreft, f.eks. brystkreft, lungekreft, kolorektal kreft, magekreft, andre kreftformer i gastrointestinaltrakten (f.eks. spiserørkreft og bukspyttkjertelkreft), prostatakreft, nyrekreft, leverkreft, blærekreft, cervikalkreft, livmorkreft, testikkelkreft, og eggstokkreft; dermatologiske tilstander slike som acne vulgaris, og anoreksi.
Behandlingen eller forebyggingen av de DGAT1-relaterte forstyrrelsene eller tilstandene listet ovenfor består av å administrere til subjektet som trenger det en terapeutisk effektiv mengde av en forbindelse beskrevet ifølge oppfinnelsen. Behandlingen kan også inkludere koadministrasjon av ytterligere terapeutiske midler.
Foretrukket er den DGAT1-assosierte forstyrrelsen svekket glukosetoleranse, type 2 diabetes og fedme.
Forbindelsene ifølge oppfinnelsen, avhengig av typen substituenter fremviser et eller flere stereogene sentere. De resulterende diastereomere, optiske isomere, dvs. enantiomerene, og de geometriske isomerene, og blandingene derav, er omfattet av foreliggende oppfinnelse.
Særlige utførelsesformer ifølge oppfinnelsen er forbindelsene:
(4-{4'-[2-(3-klor-fenylamino)-oksazol-5-yl]-bifenyl-4-yl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-klor-fenylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[6-(3-metylfenylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[6-(3-trifluormetylfenylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-metoksyfenylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[6-(2-metoksyfenylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[5-(pyridin-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre,
{4-[4-(5-fenylaminopyridin-2-yl)-fenyl]-cykloheksyl}-eddiksyre,
(4-{4-[5-(5-cyanopyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(5-trifluormetylpyridin-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(4-trifluormetylfenylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(5-metylpyridin-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(5-trifluormetylpyridin-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester,
(4-{4-[5-(5-klorpyridin-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(6-metoksypyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(3-klor-fenylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[6-(3-klor-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre,
{4-[4-(6-m-tolylamino-pyridazin-3-yl)-fenyl]-cykloheksyl}-eddiksyre, (4-{4-[6-(3-trifluormetyl-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-metoksy-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-cyano-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[6-(4-klor-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre,
{4-[4-(6-p-tolylamino-pyridazin-3-yl)-fenyl]-cykloheksyl}-eddiksyre,
(4-{4-[6-(4-trifluormetyl-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-klor-4-metoksy-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-klor-2-metyl-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, {4-[4-(6-fenylamino-pyridazin-3-yl)-fenyl]-cykloheksyl}-eddiksyre,
(4-{4-[6-(3-klor-2-metoksy-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(2-metoksy-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(4-metoksy-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(6-trifluormetyl-pyridin-3-ylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[6-(2-metyl-6-trifluormetyl-pyridin-3-ylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[6-(3-klor-2-metoksy-fenylamino)-pyridazin-3-yl]-fenyl}cykloheksyl)-eddiksyre, (4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyrazin-2-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[5-(benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester,
(4-{4-[5-(5-klor-6-metoksy-pyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[5-(3-klor-5-metyl-pyridin-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[5-(6-metyl-benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre,
(4-{4-[5-(6-klor-benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester,
(4-{4-[5-(6-klor-benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(5-klor-6-metoksy-benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, og
(4-{4-[6-(2-metyl-6-trifluormetyl-pyridin-3-ylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre,
eller i et hvilket som helst tilfelle et farmasøytisk akseptabelt salt derav.
I en ytterligere utførelsesform, er de ovenfor listede forbindelsene i form av deres korresponderende kalium-, natrium-, saltsyre-, metansulfonsyre-, fosforsyre- eller svovelsyresalter. Saltene kan fremstilles ved fremgangsmåtene beskrevet heri.
I en ytterligere særlige utførelsesform ifølge oppfinnelsen er forbindelsen:
eller et farmasøytisk akseptabelt salt derav, foretrukket på natriumsalt form.
I en ytterligere særlige utførelsesform ifølge oppfinnelsen er forbindelsen:
eller et farmasøytisk akseptabelt salt derav.
Fremgangsmåten beskrevet heri for fremstilling av forbindelser ovenfor kan utføres under inerte atmosfærer, foretrukket under nitrogenatmosfære.
I utgangsforbindelsene og intermediatene som omdannes til forbindelsene ifølge oppfinnelsen på en måte beskrevet heri, blir funksjonelle grupper tilstede, slik som amino-, tiol-, karboksyl- og hydroksylgrupper, eventuelt beskyttet ved vanlige beskyttende grupper som er vanlige innen preparativ organisk kjemi. Beskyttende amino-, tiol-, karboksyl- og hydroksylgrupper er de som kan omdannes under milde betingelser til det frie aminotiolet, karboksyl- og hydroksylgruppene uten at det molekylære rammeverket ødelegges eller andre uønskede reaksjoner finner sted.
Formålet med å introdusere beskyttende grupper er å beskytte de funksjonelle gruppene fra uønskede reaksjoner med reaksjonskomponentene under betingelsene anvendt for utføring av en ønsket kjemisk omdanning. Behovet for og valg av beskyttende grupper for en bestemt reaksjon er kjent for fagmannen og avhengig av typen funksjonell gruppe som skal beskyttes (hydroksylgruppe, aminogruppe, etc.), strukturen og stabiliteten til molekylet hvor substituenten er en del og reaksjonsbetingelsene.
Godt kjente beskyttende grupper som bemøter disse betingelsene og deres introduksjon og fjerning er beskrevet f.eks. i McOmie, ”Protective Groups in Organic Chemistry”, Plenum Press, London, NY (1973); og Greene og Wuts, ”Protective Groups in Organic Synthesis”, John Wiley & Sons, Inc., NY (1999).
De ovenfor nevnte reaksjonene utføres i henhold til standard fremgangsmåter, under nærvær eller fravær av fortynningsmiddel, foretrukket slike som er inerte ovenfor reagensene og er løsemidler derav, av katalysatorer, kondenseringsmidler og andre midler, respektivt og/eller inerte atmosfærer, ved lave temperaturer, romtemperatur eller hevede temperaturer, foretrukket ved eller nær kokepunktet til løsemidlene som anvendes og ved atmosfære eller overatmosfæretrykk. De foretrukne løsemidlene, katalysatorene og reaksjonsbetingelsene er fremsatt i vedlagte illustrative eksempler.
Foreliggende oppfinnelse inkluderer ytterligere en hvilken som helst variant av foreliggende fremgangsmåter, hvori et intermediatprodukt som oppnås ved et hvilket som helst stadie derav anvendes som utgangsmateriale og de gjenværende trinnene utføres, eller hvor utgangsmaterialene dannes in situ under reaksjonsbetingelsene, eller hvori reaksjonskomponentene anvendes i form av deres salter eller optisk rene antipoder.
Forbindelsene ifølge oppfinnelsen og intermediater kan også omdannes til hverandre i henhold til fremgangsmåter i og for seg kjente.
Avhengig av valg av utgangsmaterialer og fremgangsmåter, kan de nye forbindelsene være i form av en av de mulige isomerene eller blandinger derav, f.eks. som idet vesentlige rene geometriske (cis eller trans) isomerer, diastereomerer, optiske isomerer (antipoder), rasemater eller blandinger derav. De ovenfor angitte mulige isomerene eller blandinger derav, er innenfor omfanget av foreliggende oppfinnelse.
Hvilke som helst resulterende blandinger av isomerer kan separeres på basis av de fysiokjemiske forskjellene når det gjelder bestanddelene, i de rene geometriske eller optiske isomerene, diastereomerene, rasematene, f.eks. ved kromatografi og/eller fraksjonell krystallisasjon.
Til slutt, blir forbindelsene ifølge oppfinnelsen enten oppnådd i fri form eller i en saltform derav, foretrukket i en farmasøytisk akseptabel saltform derav.
Forbindelser ifølge oppfinnelsen som inneholder sure grupper kan omdannes til salter med farmasøytisk akseptable baser. Slike salter inkluderer alkalimetallsalter, som natrium-, litium- og kaliumsalter; jordalkalimetallsalter, som kalsium- og magnesiumsalter; ammoniumsalter med organiske baser, f.eks. trimetylaminsalter, dietylaminsalter, tris(hydroksymetyl)aminsalter, dicykloheksylaminsalter og N-metyl-D-glukaminsalter; salter med aminosyrer som arginin, lysin og lignende. Salter kan dannes ved anvendelse av vanlige fremgangsmåter, fordelaktig under nærvær av et eter- eller alkoholløsemiddel, slik som en lavere alkohol. Fra løsningene av sistnevnte kan saltene presipitere med etere, f.eks. dietyleter eller acetonitril. De resulterende saltene kan omdannes til de frie forbindelsene ved behandling med syrer. Disse og andre salter kan også anvendes for rensing av forbindelsene som oppnås.
Alternativt kan alkalimetallsalter av sure forbindelser også fremstilles fra den korresponderende esteren, dvs. metyl- eller etylkarboksylsyreesteren. Behandling av den passende esteren med en alkalisk base slik som natrium, kalium eller litiumhydroksid i et eter- eller alkoholløsemiddel kan direkte gi alkalimetallsaltet, som kan presipiteres fra en reaksjonsblanding ved tilsetning av et koløsemiddel slik som dietyleter eller acetonitril.
Forbindelser ifølge oppfinnelsen kan generelt omdannes til syreaddisjonssaltene, særlig farmasøytisk akseptable salter. Disse dannes f.eks. med uorganiske syrer, slik som mineralsyrer, f.eks. svovelsyre, fosforsyre eller hydrohalosyre, eller med organiske karboksylsyrer, slike som (C1-C4)-alkankarboksylsyrer som f.eks. er usubstituerte eller substituerte med halogen, f.eks. eddiksyre, slike som mettede eller umettede dikarboksylsyrer, f.eks. oksalsyre, ravsyre, maleinsyre eller fumarsyre, slik som hydroksykarboksylsyrer, f.eks. glykolsyre, melkesyre, eplesyre, vinsyre eller sitronsyre, slik som aminosyrer, f.eks. aspartansyre eller glutamsyre, eller med organiske sulfonsyrer, slike som (C1-C4)-alkylsulfonsyrer, f.eks. metansulfonsyre; eller arylsulfonsyrer som er usubstituerte eller substituerte (f.eks. med halogen). Foretrukket er salter dannet med saltsyre, maleinsyre og metansulfonsyre.
Disse saltene kan fremstilles ved suspensjon eller oppløsning av de foretrukne forbindelsene i et organisk løsemiddel eller vann eller passende blanding av de to, fulgt av tilsetning av den passende syren. Det resulterende saltet kan isoleres ved presipitasjon og/eller fjerning av løsemiddel. Presipitasjon av saltet kan bedres ved tilsetning av koløsemidler slik som eterløsemidler eller acetonitril, avkjøling, såing eller andre fremgangsmåter kjente for fagmannen.
I lys av det nære slektskapet mellom de frie forbindelsene og forbindelsene i form av deres salter, er det når en forbindelse refereres til i denne sammenheng også ment et korresponderende salt , forutsatt at slikt er mulig eller passende under omstendighetene.
Forbindelsene, som inkluderer deres salter, kan også oppnås i form av deres hydrater, eller inkludere andre løsemidler anvendt for deres krystallisering.
Slik det er beskrevet heri ovenfor, kan forbindelsene ifølge oppfinnelsen anvendes for behandling av tilstander mediert ved DGAT1-aktivitet. Slike forbindelser kan således anvendes terapeutisk for behandling av svekket glukosetoleranse, type 2 diabetes og fedme.
Foreliggende oppfinnelse tilveiebringer videre farmasøytiske sammensetninger som innbefatter en terapeutisk effektiv mengde av en farmakologisk aktiv forbindelse ifølge oppfinnelsen, alene eller i kombinasjon med en eller flere farmasøytisk akseptable bærere.
De farmasøytiske sammensetningene ifølge oppfinnelsen er de som er egnet for enteral, slik som oral eller rektal; transdermal og parenteral administrasjon til pattedyr, som inkluderer mennesker, for behandling av tilstander mediert ved DGAT1-aktivitet. Slike tilstander inkluderer svekket glukosetoleranse, type 2 diabetes og fedme.
Således kan de farmakologisk aktive forbindelsene ifølge oppfinnelsen anvendes for fremstilling av farmasøytiske sammensetninger som innbefatter en effektiv mengde derav i forbindelse med eller sammenblandet med eksipienter eller bærere egnet for enten enteral eller parenteral anvendelse. Foretrukket er tabletter og gelatinkapsler som innbefatter den aktive ingrediensen sammen med:
a) fortynningsmidler, f.eks. laktose, dekstrose, sukrose, mannitol, sorbitol, cellulose og/eller glycin;
b) smøremidler, f.eks. silika, talkum, stearinsyre, dens magnesium- eller kalsiumsalt og/eller polyetylenglykol; for tabletter også
c) bindemidler, f.eks. magnesiumaluminiumsilikat, stivelsepasta, gelatin, tragakant, metylcellulose, natriumkarboksymetylcellulose og/eller polyvinylpyrrolidon; hvis ønskelig
d) disintegreringsmidler, f.eks. stivelser, agar, algininsyre eller dens natriumsalt eller bruseblandinger; og/eller
e) absorbenter, fargestoffer, smaksstoffer og søtningsstoffer.
Injiserbare sammensetninger er foretrukket vandige isotone løsninger eller suspensjoner og stikkpiller blir fordelaktig fremstilt fra fettemulsjoner eller suspensjoner.
Nevnte sammensetninger kan steriliseres og/eller inneholde adjuvanter slike som konserveringsmidler, stabilisesringsmiddel, fuktemiddel eller emulgeringsmidler, løsningspromotere, salter for å regulere det osmotiske trykket og/eller buffere. I tillegg kan de også inneholde andre terapeutisk verdifulle substanser. Nevnte sammensetninger fremstilles i henhold til vanlig sammenblanding, granulering eller belegningsfremgangsmåter, respektivt, og inneholder ca.0,1-75%, foretrukket ca.1-50% av den aktive ingrediensen.
Egnede formuleringer for transdermal anvendelse inkluderer en terapeutisk effektiv mengde av en forbindelse ifølge oppfinnelsen med bærer. Fordelaktige bærere inkluderer absorberbare farmakologisk akseptable løsemidler for å assistere passering gjennom huden til verten. Karakteristisk er de transdermale innretningene i form av en bandasje som innbefatter en baksidedel, et reservoar som inneholder forbindelsen eventuelt med bærere, eventuelt en hastighetskontrollerende barriere for å levere forbindelsen til huden til verten ved en kontrollert og forhåndsbestemt hastighet over en forlenget tidsperiode, og midler for å sikre innretningen til huden.
De farmasøytiske sammensetningene kan inneholde en terapeutisk effektiv mengde av en forbindelse ifølge oppfinnelsen slik det er definert ovenfor, enten alene eller i en kombinasjon med andre terapeutiske midler, f.eks., hver ved en terapeutisk effektiv dose slik det er rapportert i litteraturen. Slike terapeutiske midler inkluderer:
a) antidiabetiske midler, slike som insulin, insulinderivater og mimetiske midler; insulinutskillende forbindelser slike som sulfonylureaforbindelser, f.eks. glipizid, glyburid og amaryl; insulinotropiske sulfonylureareseptorligander slike som meglitinider, f.eks. nateglinid og repaglinid; proteintyrosinfosfatase-1B (PTP-1B) inhibitorer slike som PTP-112; GSK3 (glykogen syntasekinase-3) inhibitorer, slik som SB-517955, SB-4195052, SB-216763, NN-57-05441 og NN-57-05445; RXR-ligander slike som GW-0791 og AGN-194204; natriumavhengige glukosekotransporterinhibitorer slike som T-1095; glykogenfosforylase A-inhibitorer slike som BAY R3401; biguanider slik som metformin; �-glukosidaseinhibitorer slik som akarbose; GLP-1 (glukagonlignende peptid-1), GLP-1-analoger slike som Exendin-4 og GLP-1-mimetiske midler; og DPPIV (dipeptidylpeptiase IV) -inhibitorer slike som vildagliptin;
b) hypolipidemiske midler slike som 3-hydroksy-3-metyl-glutaryl koenzym A (HMG-CoA) reduktaseinhibitorer, f.eks. lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin og rivastatin; squalensyntaseinhibitorer; FXR (farnesoid X-reseptor) og LXR (lever X-reseptor) ligander; kolestyramin; fibrater; nikotinsyregallesyrebindende harpikser slike som kolestyramin; fibrater; nikotinsyre og andre GPR109-agonister; kolesterolabsorpsjonsinhibitorer slike som ezetimib; CETP-inhibitorer (kolesterol-esteroverførings-proteininhibitorer) og aspirin;
c) anti-fedmemidler slike som orlistat, sibutramin og kannabinoidreseptor 1 (CB1) antagonister f.eks. rimonabant; og
d) anti-hypertensive midler, f.eks. loopdiuretiske midler slike som etakrynsyre, furosemid og torsemid; angiotensinomdannende enzym (ACE) -inhibitorer slike som benazepril, kaptopril, enalapril, fosinopril, lisinopril, moeksipril, perinodopril, quinapril, ramipril og trandolapril; inhibitorer av Na-K-ATPase-membranpumpen slike som digoksin; neutralendopeptidase (NEP) -inhibitorer; ACE/NEP-inhibitorer slike som omapatrilat, sampatrilat og fasidotril; angiotensin II-antagonister slike som kandesartan, eprosartan, irbesartan, losartan, telmisartan og valsartan, særlig valsartan; renininhibitorer slike som ditekiren, zankiren, terlakiren, aliskiren, RO 66-1132 og RO-66-1168; β-adrenergiske reseptorblokkerere slike som acebutolol, atenolol, betaksolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol og timolol; inotropiske midler slike som digoksin, dobutamin og milrinon; kalsiumkanalblokkerere slike som amlodipin, bepridil, diltiazem, felodipin, nikardipin, nimodipin, nifedipin, nisoldipin og verapamil; aldosteronreseptorantagonister; og aldosteronsyntaseinhibitorer;
e) agonister av peroksisomproliferatoraktivatorreseptorer, slike som fenofibrat, pioglitazon, rosiglitazon, tesaglitazar, BMS-298585, L-796449, forbindelsene spesifikt beskrevet i patentsøknad WO 2004/103995 dvs. forbindelser i eksempel 1 til 35 eller forbindelser spesifikt listet i krav 21, eller forbindelsene spesifikt beskrevet i patentsøknad WO 03/043985, dvs. forbindelser i eksemplene 1 til 7 eller forbindelser spesifikt listet i krav 19 og særlig (R)-1-{4-[5-metyl-2-(4-trifluormetyl-fenyl)-oksazol-4-ylmetoksy]-benzensulfonyl}-2,3-dihydro-1H-indol-2-karboksylsyre eller et salt derav.
Således dekker foreliggende oppfinnelse farmasøytiske sammensetninger som innbefatter:
i) en forbindelse ifølge oppfinnelsen som definert ovenfor, og
ii) minst en forbindelse valgt fra
a) antidiabetiske midler,
b) hypolipidemiske midler,
c) anti-fedmemidler,
d) anti-hypertensive midler,
e) agonister av peroksisomproliferatoraktivatorreseptorer,
iii) en eller flere farmasøytisk akseptable bærere.
Andre spesifikke anti-diabetiske forbindelser er beskrevet av Patel Mona i Expert Opin Investig Drugs, 2003, 12(4), 623-633, i figurene 1 til 7. En forbindelse ifølge oppfinnelsen kan administreres enten simultant, før eller etter den andre aktive ingrediensen, enten separat ved samme eller forskjellig rute for administrasjon eller sammen i samme farmasøytiske formulering.
Strukturen til de terapeutiske midlene identifisert ved kodetall, generiske eller varemerkenavn kan tas fra den aktuelle utgaven av standardkompendiet ”The Merck Index” eller fra databaser, f.eks. Patents International (f.eks. IMS World Publications).
Følgelig tilveiebringer foreliggende oppfinnelse farmasøytiske sammensetninger som innbefatter en terapeutisk effektiv mengde av en forbindelse ifølge oppfinnelsen i kombinasjon med en terapeutisk effektiv mengde av et annet terapeutisk middel, foretrukket valgt fra anti-diabetiske midler, hypolipidemiske midler, anti-fedmemidler eller antihypertensive midler, mest foretrukket fra anti-diabetiske midler eller hypolipidemiske midler slik det er beskrevet ovenfor.
En enhetsdosering for et pattedyr på ca.50-70 kg kan inneholde mellom ca. 1 mg og 1000 mg, fordelaktig mellom ca.5 mg og 500 mg av den aktive ingrediensen. Den terapeutisk effektive doseringen av aktiv forbindelse er avhengig av arten av det varmblodige dyret (pattedyret), kroppsvekten, alderen og den individuelle tilstanden, av administrasjonsformen og forbindelsen som er involvert.
I henhold til det som er angitt ovenfor, tilveiebringer foreliggende oppfinnelse også en terapeutisk kombinasjon, f.eks. et kitt, kitt av deler, f.eks. for anvendelse slik det er de finert heri, som innbefatter en forbindelse ifølge kravene og beskrevet ovenfor, eller et farmasøytisk akseptabelt salt derav, som anvendes samtidig med eller i sekvens med minst en farmasøytisk sammensetning som innbefatter minst et annet terapeutisk middel, foretrukket valgt fra anti-diabetiske midler, hypolipidemiske midler, antifedmemidler og anti-hypertensive midler, eller et farmasøytisk akseptabelt salt derav. Kittet kan innbefatte instruksjoner for dets administrasjon. Kombinasjonen kan være en fiksert kombinasjon (f.eks. i samme farmasøytiske sammensetning) eller en fri kombinasjon (f.eks. i separate farmasøytiske sammensetninger).
Tilsvarende tilveiebringer foreliggende oppfinnelse et kitt av deler som innbefatter: (i) en farmasøytisk sammensetning ifølge oppfinnelsen; og (ii) en farmasøytisk sammensetning som innbefatter en forbindelse valgt fra et anti-diabetisk middel, et hypolipidemisk middel, et anti-fedmemiddel og et anti-hypertensivt middel, eller et farmasøytisk akseptabelt salt derav, i form av to separate enheter av komponenter (i) til (ii).
Foretrukket blir en forbindelse ifølge oppfinnelsen administrert til et pattedyr som trenger det.
Foretrukket blir en forbindelse ifølge oppfinnelsen anvendt for behandling av en sykdom som responderer på modulering av DGAT1-aktiviteten.
Foretrukket er tilstanden assosiert med DGAT1-aktivitet valgt fra svekket glukosetoleranse, type 2 diabetes og fedme.
Slik det anvendes i foreliggende beskrivelse og i kravene, omfatter begrepet ”behandling” alle de forskjellige formene og måtene for behandling slik det er kjent for fagmannen og inkluderer særlig preventiv, kurativ, forsinkning av progresjon og lindrende behandling.
De ovenfor angitte egenskapene demonstreres i in vitro og in vivo tester ved anvendelse av fordelaktige pattedyr, f.eks. mus, rotter, hunder, aper eller isolerte organer, vev og preparater derav. Nevnte forbindelser kan anvendes in vitro i form av løsninger, f.eks. foretrukket vandige løsninger, og in vivo enten enteralt, parenteralt, fordelaktig intravenøst, f.eks. som en suspensjon eller i vandig løsning. Doseringen in vitro kan variere fra mellom ca. 10<-2>molar og 10<-9>molar konsentrasjoner. En terapeutisk effektiv mengde in vivo kan variere, avhengig av administrasjonsruten, fra mellom ca.0,1 mg/kg til 1000 mg/kg, foretrukket mellom ca.1 mg/kg og 100 mg/kg.
Aktiviteten til forbindelsene ifølge oppfinnelsen kan bestemmes ved følgende fremgangsmåter eller fremgangsmåter beskrevet i litteraturen:
Enzympreparatet anvendt i denne undersøkelsen er et membranpreparat fra Sf9-celler som overuttrykker human (His)6DGAT1. I løpet av alle trinnene, blir prøvene avkjølt til 4ºC. Sf9-celler som uttrykker human (His)6DGAT1 ble tint ved romtemperatur og resuspendert ved et 10:1 forhold (ml buffer/g celler) i 50 mM HEPES, 1x fullstendig proteaseinhibitor, pH 7,5.
De resuspenderte pelletsene ble homogenisert i 1 minutt ved anvendelse av en Brinkman PT 10/35 homogeniserer med en 20 mm generator. Cellene ble lysert ved anvendelse av Avestin Emulsiflex (avkjølt til 4ºC) ved 10000-15 000 psi. Lysat ble sentrifugert ved 100000 x g i 1 time ved 4ºC. Supernatant ble fjernet og pellets ble resuspendert i 50 mM HEPES, 1x fullstendig proteaseinhibitor, pH 7,5 ved 1/6 av volumet til supernatanten. Resuspenderte pellets ble oppsamlet og homogenisert med 10 slag med en Glas-Col motordreven teflonstempel med innstilling 70. Proteinkonsentrasjonen av membranpreparatet ble kvantifisert ved anvendelse av BCA proteinundersøkelse med 1% SDS. Membranpreparatet ble alikvotert, frosset på tørris og lagret ved -80ºC.
For 50 ml, ble 25 ml 0,2M HEPES forrådsbuffer, 0,5 ml 1M MgCl2(5 mM sluttkonsentrasjon) og 24,5 ml milli-Q H2O tilsatt til 55 ml Wheaton Potter-Elvehjem homogeniserer. Enzympreparat (0,1 ml) tilsettes til buffer og blandingen homogeniseres med 5 slag på is ved anvendelse av Glas-Col variabel hastighetshomogeniseringssystem på innstilling 70.
For 50 ml, ble 0,5 ml 10 mM diolein tilsatt til 9,5 ml EtOH i et 50 ml Falcon-skruhette konisk sentrifugerør. 5 ml 10 mM natriumacetat pH 4,5 ble tilsatt fulgt av 0,5 ml 10 mM oleoyl-CoA. Til slutt ble gjenværende 4,5 ml av 10 mM natriumacetat pH 4,5 tilsatt fulgt av 30 ml milli-Q H2O. Løsningen bør røres forsiktig for hånd for å indusere sammenblanding. Sluttkonsentrasjonene av EtOH og natriumacetat er 20% og 2 mM, respektivt.
Tørre forbindelser løses i passende volum DMSO ved en sluttkonsentrasjon på 10 mM. En 10 punkts tre ganger doserespons anvendes for å evaluere forbindelsespotensialet. Alle fortynninger utføres i DMSO i en Greiner 384-brønns mikroplate.
1. 2 µl forbindelse i DMSO tilsettes til passende brønner.2 µl DMSO tilsettes til 100% aktivitet og 100% inhiberingskontroller.
2. 25 µl enzymblanding tilsettes til alle brønnene og platene inkuberes i 10 minutter ved romtemperatur.
3. 10 µl 20% eddiksyrestoppløsning tilsettes til 100% inhiberingskontrollbrønner. Platene virvles ved anvendelse av Troemner multirørvirvler (innstilling 7 i 10 sekunder).
4. 25 µl substratblanding tilsettes til alle brønnene. Platene virvles ved anvendelse av Troemner multirørvirvler (innstilling 7 i 10 sekunder). Platene inkuberes i 30 minutter ved romtemperatur.
5. 10 µl 20% eddiksyrestoppløsning tilsettes til alle brønnene. Platene virvles ved anvendelse av Troemner multirørvirvler (innstilling 7 i 10 sekunder).
6. 50 µl 1-butanol vekt/glyseryltripalmitoleat indre standard tilsettes til alle brønnene.
7. Platene forsegles med superpierce sterk plateforsegler ved anvendelse av termoforsegleren.
8. Platene virvles ved anvendelse av Troemner multirørvirvler (innstilling 10 i 5 minutter).
9. Platene sentrifugeres ved 162 x g (1000 rpm for GH-3,8 rotor) i 5 minutter ved anvendelse av Beckman GS-6R bordsentrifuge.
Prøvene analyseres med LC/MS/MS ved anvendelse av en Waters 1525 µ LC og Quattro Micro API MS. Der det er indikert, ble tripalmitolein anvendt som indre standard for å kontrollere for instrumentvariasjon.
Data omdannes til % inhibering før kurvetilpassing ved anvendelse av følgende ligning:
% inhibering = (respons forbindelse - respons 100% inhiberingskontroll) x 100
(respons 100% aktivitetskontroll - respons 100% inhiberingskontroll)
Ved anvendelse av fremgangsmåten beskrevet ovenfor, viste forbindelsene ifølge oppfinnelsen seg å fremvise inhiberingsaktivitet med IC50-verdier varierende fra 0,001 uM til 100 uM.
Tabell 1 viser inhiberingsaktivitet (IC50-verdier) til en representativ forbindelse ovenfor human DGAT1.
Forbindelsene ifølge oppfinnelsen kan fremstilles fra kommersielt tilgjengelige reagenser ved anvendelse av generelle synteseteknikker kjente for fagmannen. Angitt nedenfor er reaksjonsskjemaer egnet for fremstilling av slike forbindelser. Videre, blir eksemplifisering funnet i de spesifikke eksemplene som er tilveiebragt.
Skjema 3
For forbindelser ifølge oppfinnelsen hvor B er en oksazolring, kan den generelle syntesesekvensen beskrevet i skjema 3 anvendes. Omdanning av bromacetofenonderivatet til det korresponderende azidointermediatet kan skje via reaksjon med natrium- eller litiumazid i et organisk løsemiddel som kan eller kan ikke inneholde vann. Azidoketonintermediatet kan deretter behandles med et triaryl- eller trialkylfosfin (slik som trifenylfosfin) under nærvær av et isotiocyanat for å gi det korresponderende aminooksazolet. Denne cykliseringen krever ofte oppvarming, slik det er beskrevet av Dhar et al. i Bioorg. Med. Chem. Lett.12 (2002), 3125-3128.
Skjema 4
For forbindelser ifølge oppfinnelsen hvor B er en pyridinring, kan den generelle syntesesekvensen beskrevet i skjema 4 anvendes. Et aminoderivat kan omsettes med et passende pyridinderivat for å gi det korresponderende aminopyridinintermediatet. For eksempel, når Y er en passende plassert utgående gruppe (dvs. i 2- eller 4-posisjonen) slik som halogenatom, toluensulfonat, metansulfonat eller trifluormetansulfonat, kan aminoderivatet R1NH2omsettes under nærvær av syre (slik som HCl eller svovelsyre) eller base (slik som natriumhydrid, trietylamin eller DBU) for å gi aminopyridinintermediatet. Anvendelsen av overgangsmetaller slik som palladium eller kobber kan også gi denne omdanningen, uansett om Y utelates. Alternativt kan kobbersalter mediere prosessen hvor Y er en borsyre eller esterderivat [se Tet. Lett. (1998), bind 39, s.2941]. Det resulterende aminopyridinderivatet kan deretter kobles til aryl-W-intermediatet ovenfor ved anvendelse av overgangsmetallkatalysert krysskoblingsmetodologi. For eksempel, hvor W er en borsyre/ester, trialkyltinn eller trialkylsilan, kan den passende aryl-X-partneren, hvor X er et halogenatom eller sulfonat, reagere under nærvær av et overgangsmetall slik som palladium med eller uten en støttende ligand for å gi karbonkarbonbindingkonstruksjon. Alternativt kan W og X reverseres i denne bindingsavkoblingen.
Alternativt kan sekvensen ovenfor utføres med annen rekkefølge som følger:
I skjemaet ovenfor, kan W være en borsyreester eller passende ekvivalent, X kan være et halogen eller passende sulfonat og Y kan være en nitrogenforløper slik som nitro eller beskyttet nitrogen slik som NHBoc. Y kan deretter elaboreres til det korresponderende aminoderivatet, som deretter kan kobles med det passende R1-X-derivatet under sure, basiske eller metallfremmende betingelser slik det er beskrevet ovenfor.
Skjema 5
For forbindelser ifølge oppfinnelsen hvor B er en pyridazinring, kan syntesesekvensen vist i skjema 5 anvendes. Et difunksjonalisert pyridazinintermediat, f.eks.3,6-diklorpyridazin, kan omsettes med en aminonukleofil R1NH2under nærvær av en syre (slik som HCl eller svovelsyre) eller base (slik som natriumhydrid, trietylamin eller DBU) for å gi aminopyridazinintermediatet. Anvendelsen av overgangsmetaller slike som palladium eller kobber kan også lette denne omdanningen, uansett om X og Y utelates. Det resulterende aminopyridazinderivatet kan deretter kobles til aryl-W-intermediatet ovenfor ved anvendelse av overgangsmetallkatalysert krysskoblingsmetodologi. For eksempel, hvor W er en borsyre/ester, trialkyltinn eller trialkylsilan, kan den passende aryl-X-partneren hvor X er et halogenatom eller sulfonat, omsettes under nærvær av et overgangsmetall slik som palladium med eller uten en støttende ligand for å gi denne karbon-karbonbindingskonstruksjonen. Alternativt kan W og X reverseres i denne bindingsfrakoblingen.
Skjema 6
Forbindelsene ifølge oppfinnelsen hvor B er en pyridazinring kan også fremstilles ved syntesesekvensen vist i skjema 6. Acylering av utgangsarenderivatet med det passende karboksylsyrederivatet (dvs. et syreklorid) under nærvær av en Lewis-syre slik som aluminiumtriklorid, kan gi acetofenonderivatet slik det er vist. Konstruksjon av pyridazonringen kan utføres analogt med litteraturbeskrivelsen (Synthesis (1993), s. 334). Aktivering av pyridazonintermediatet via klor- eller brompyridazin kan utføres via fosforoksyklorid, fosforbromid eller ekvivalent aktiveringsreagens. Substitusjon med aminet R1-NH2kan deretter skje under sure, basiske eller overgangsmetallfremmede betingelser.
Skjema 7
For forbindelser ifølge oppfinnelsen hvor B er en pyridazinring, kan syntesesekvensen vist i skjema 7 anvendes. Et difunksjonelt pyrazinintermediat kan omsettes med en aminonukleofil R1NH2under nærvær av syre (slik som HCl eller svovelsyre) eller base (slik som natriumhydrid, trietylamin eller DBU) for å gi aminopyridinintermediatet. Anvendelsen av overgangsmetaller slik som palladium eller kobber kan også lette denne omdanningen, uansett om X og Y utelates. Det resulterende aminopyrazinderivatet kan deretter funksjonaliseres med en X-gruppe slik som halogen eller sulfonat, deretter kobles til aryl-W-intermediatet ovenfor ved anvendelse av overgangsmetallkatalysert krysskoblingsmetodologi. For eksempel, hvor W er en borsyre/ester, trialkyltinn eller trialkylsilan, kan den passende aryl-X-partneren omsettes under nærvær av et overgangsmetall slik som palladium med eller uten en støttende ligand for å gi denne karbon-karbonbindingskonstruksjonen. Alternativt kan W og X reverseres i denne bindingsfrakoblingen.
EKSEMPLER
Følgende eksempler er tiltenkt å illustrere oppfinnelsen og er ikke konstruert som noen begrensning av oppfinnelsen. Hvis ikke annet er nevnt på annen måte, blir alle fordampninger utført under redusert trykk, foretrukket mellom ca.50 mm Hg og 100 mm Hg. Strukturen til sluttproduktene, intermediatene og utgangsmaterialene ble bekreftet ved standard analytiske metoder, f.eks. mikroanalyse, smeltepunkt (smp.) og spektroskopiske karakteristikker, f.eks. MS, IR og NMR. Forkortelser som anvendes er de som er vanlige i litteraturen.
HPLC-betingelser:
A: Inertsil 4,6 mm x 5 cm C8-3 kolonne, 10 til 90% acetonitril i 5 mM ammoniumformat, 2 min. gradient, 4 ml/min., 50ºC.
B: Inertsil 4,6 mm x 5 cm C8-3 kolonne, 40 til 90% acetonitril i 5 mM ammoniumformat, 2 min. gradient, 4 ml/min., 50ºC.
C: Inertsil 4,6 mm x 5 cm C8-3 kolonne, 40 til 90% acetonitril i 0,1% eddiksyre, 2 min. gradient, 4 ml/min., 50ºC.
D: Kolonne: Atlantis C18 (Waters, Inc.), 50 cm x 4,6 mm x 5 µm.
Kolonnetemperatur: omgivelsestemperatur.
Strømningshastighet: 1,4 ml/min.
Injeksjonsvolum: 3,0 µl.
Gradient: A = 0,1% trifluoreddiksyre (TFA) i vann
B = 0,0,5% trifluoreddiksyre (TFA) i acetonitril
0-95% B i løpet av 19,0 min., 1,8 min. hold.
E: Gemini C18 4,6 x 50 mm, 5 µm partikkelstørrelse; 5-100% ACN/H2O 5 mM NH4OH/8 min.
Eksempel 3-1
(4-{4-[2-(3-klorfenylamino)-oksazol-5-yl]-fenyl}-cykloheksyl)-eddiksyre
A. {4-[4-(2-azidoacetyl)-fenyl]-cykloheksyl}-eddiksyre etylester
Til en løsning av {4-[4-(2-bromacetyl)-fenyl]-cykloheksyl}-eddiksyre etylester (166 mg, 0,451 mmol) i aceton/vann (4:1, volum/volum, 5 ml) tilsettes NaN3(44 mg, 0,676 mmol) og blandingen røres ved omgivelsestemperatur i 2 timer. Vann (10 ml) tilsettes og EtOAc anvendes for å ekstrahere blandingen. Den organiske fasen tørkes med MgSO4, konsentreres og tørkes under høyvakuum for å gi tittelforbindelsen (154 mg).
1H NMR (400 MHz, kloroform-d) δppm 1,05 - 1,16 (m, 2 H) 1,20 (t, J=7,07 Hz, 3 H) 1,40 - 1,49 (m, 2 H) 1,84 (d, J=10,11 Hz, 4 H) 1,76 - 1,87 (m, 1 H) 2,17 (d, J=6,82 Hz, 2 H) 2,48 (tt, J=12,25, 3,03 Hz, 1 H) 4,08 (q, J=7,16 Hz, 2 H) 4,45 (s, 2 H) 7,25 (d, J=8,34 Hz, 2 H) 7,76 (d, J=8,34 Hz, 2H).
B. (4-{4-[2-83-klorfenylamino)-oksazol-5-yl]-fenyl}-cykloheksyl)-eddiksyre etylester
Til en løsning av {4-[4-(2-azidoacetyl)-fenyl]-cykloheksyl}-eddiksyre etylester (154 mg, 0,967 mmol) i 1,4-dioksan (5 ml) tilsettes trifenylfosfin (122 mg, 0,967 mmol) og 1-klor-3-isotiocyanatobenzen (0,051 ml, 0,389 mmol). Reaksjonsblandingen blir deretter varmet opp til 90ºC i 30 minutter. Vann (10 ml) tilsettes og EtOAc (20 ml) anvendes for å ekstrahere blandingen. Den organiske fasen vaskes med saltvann (1x15 ml), tørkes med MgSO4og konsentreres som gir tittelforbindelsen (109 mg) som et offwhite faststoff.
1H NMR (400 MHz, DMSO-d6) d ppm 1,19 (t, J=7,20 Hz, 3 H) 1,12 - 1,19 (m, 2 H) 1,43 - 1,52 (m, 2 H) 1,81 (d, J=10,61 Hz, 4 H) 1,73 - 1,84 (m, 1 H) 2,23 (d, J=6,82 Hz, 2 H) 4,07 (q, J=7,07Hz, 2 H) 6,99 (ddd, J=7,83, 2,02, 0,76 Hz, 1 H) 7,28 - 7,36 (m, 3 H) 7,41 (s, 1 H) 7,47 - 7,53 (m, 3 H) 7,85 (t, J=2,02 Hz, 1 H) 10,52 (s, 1 H);
(M+H)+ 439,2.
C. (4-{4-[2-(3-klorfenylamino)-oksazol-5-yl]-fenyl}-cykloheksyl)-eddiksyre Til en løsning av (4-{4-[2-(3-klorfenylamino)-oksazol-5-yl]-fenyl}-cykloheksyl)-eddiksyre etylester (0,10 g) i 6 ml THF/vann (2:1) tilsettes 2 ml av en 10% vandig LiOH-løsning. Reaksjonsblandingen varmes opp til 150ºC under mikrobølgeoppvarming i 20 minutter. Surgjøring med konsentrert HCl gir et presipitat som filtreres for å gi tittelforbindelsen.
<1>H NMR (400 MHz, DMSO-d6) d ppm 1,14 - 1,25 (m, 2 H) 1,48 - 1,60 (m, 2 H) 1,76 -1,83 (m, 1 H) 1,86 - 1,94 (m, 4 H) 2,21 (d, J=7,07 Hz, 2 H) 7,06 (dd, J=8,21, 1,64 Hz, 1 H) 7,34 - 7,43 (m, 3 H) (s, 1 H) 7,53 - 7,59 (m, 3 H) 7,91 (t, J=2,02 Hz, 1 H) 10,59 (s, 1 H) 12,03 (br, s, 1H);
MS (M+H)<+>= 411,1.
Alternativt, kan metylesteren løses i THF og behandles med vandig natriumhydroksid (4 ekv.). Blandingen kan deretter røres ved 50ºC i 12 timer, hvorved vann kan tilsettes og det meste av det organiske løsemidlet kan fjernes under redusert trykk. Tilsetting av acetonitril fulgt av avkjøling kan gi et presipitat som kan isoleres ved filtrering for å gi tittelforbindelsen som det korresponderende natriumsaltet.
Følgende forbindelser fremstilles på analog måte:
Eksempel 4-3
(4-{4-[6-(3-klor-fenylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre
A. (5-brom-pyridin-2-yl)-(3-klorfenyl)-amin
En 1 drams beholder ble tilsatt 2,5-dibrompyridin (0,5 g, 2,1 mmol, 1,0 ekv.) og 3-klorfenylamin (0,89 ml, 8,4 mmol, 4 ekv.). Den rene reaksjonsblandingen ble varmet opp til 180ºC i 3 timer. Reaksjonsblandingen ble avkjølt og deretter renset med flashkromatografi som ga tittelforbindelsen.
(M+H)+ 285,0.
B. (4-{4-[6-(3-klor-fenylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre Tittelforbindelsen ble syntetisert ved anvendelse av {4-[4-(4,4,5,5-tetrametyl-[1,3,2]dioksaborolan-2-yl)-fenyl]-cykloheksyl}-eddiksyre metylester og fremgangsmåtene beskrevet ovenfor.
<1>H NMR (400 MHz, DMSO-d6) δ� 1,30 - 1,36 (m, 1 H) 1,65 – 1,78 (m, 1 H) 1,85 (m, 5 H) 1,89 - 1,97 (m, 1 H) 2,00 - 2,11 (m, 1 H) 2,53 (d, J=7,58 Hz, 2 H) 2,80 (d, J=9,60 Hz, 1 H) 7,16 (t, J=8,21 Hz, 2 H) 7,57 (d, J=8,34 Hz, 2 H) 7,52 (t, J=8,08 Hz, 2 H) 7,81 (d, J=8,08 Hz, 2 H) 7,74 - 7,83 (m, 1 H) 8,15 (dd, J=8,59, 2,53 Hz, 1 H) 8,31 (t, J=2,02 Hz, 1 H) 8,76 (d, J=2,78 Hz, 1 H) 9,65 (s, 1 H);
(M+H)+ 421,2.
Følgende forbindelser kan fremstilles på analog måte ved anvendelse av passende anilin:
Eksempel 4-12
(4-{4-[6-(2-metyl-6-trifluormetyl-pyridin-3-ylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre
A. (5-brom-pyridin-2-yl)-(2-metyl-trifluormetyl-pyridin-3-yl)-amin
2,5-dibrompyridin (474 mg, 2 mmol) og 2-metyl-6-trifluormetyl-pyridin-3-ylamin (352 g, 2 mmol) ble løst i 1,4-dioksan (4 ml) i et trykkar. Pd2dba3(55 mg, 0,06 mmol) og XANTPHOS (46 mg, 0,08 mmol) ble tilsatt fulgt av cesiumkarbonat (1,3 g, 4 mmol). Blandingen ble overstrømmet med nitrogen i 10 minutter og deretter ble karet forseglet og varmet opp til 100ºC i 18 timer. Blandingen ble fordelt mellom EtOAc og mettet vandig NH4Cl, og deretter ble det organiske sjiktet vasket med saltvann, tørket med magnesiumsulfat, filtrert og konsentrert med rotasjonsfordampning. Det urene materialet ble renset med kolonnekromatografi på silikagel, eluert med en gradient av EtOAc/heksan (7-60%) som ga målforbindelsen som et faststoff.
<1>H NMR (400 MHz, CDCl3) δ ppm 2,62 (s, 3 H) 6,36 (br, s, 1 H) 6,75 (d, J=8,59 Hz, 1 H) 7,53 (d, J=8,34 Hz, 1 H) 7,69 (dd, J=8,84, 2,53 Hz, 1 H) 8,32 - 8,37 (m, 2 H); MS (M+H)+ 334,7.
B. (4-{4-[6-(2-metyl-6-trifluormetyl-pyridin-3-ylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre metylester
(5-brom-pyridin-2-yl)-(2-metyl-6-trifluormetyl-pyridin-3-yl)-amin (290 mg, 0,87 mmol) og {4-[4-(4,4,5,5-tetrametyl-[1,3,2]dioksaborolan-2-yl)-fenyl]-cykloheksyl}-eddiksyre metylester (312 mg, 0,87 mmol) ble løst i vannfri DME (3 ml) i et trykkar. PdCl2dppf (21 mg, 0,026 mmol) ble tilsatt, fulgt av vandig natriumkarbonat (2M, 0,870 ml, 1,74 mmol). Blandingen ble overstrømmet med nitrogen i 10 minutter og deretter ble karet forseglet og varmet opp til 80ºC i 18 timer. Blandingen ble fordelt mellom EtOAc og vann, vasket med saltvann, tørket med magnesiumsulfat, filtrert og konsentrert med rotasjonsfordampning. Det urene materialet ble renset med kolonnekromatografi på silikagel, eluert med en gradient av EtOAc/heksan (7-50%) som ga målforbindelsen som et fast stoff.
<1>H NMR (400 MHz, DMSO-d6) δ�ppm� 1,08 - 1,21 (m, 2 H) 1,50 (td, J=12,44, 10,23 Hz, 2 H) 1,81 (m, 4 H) 2,25 (d, J=6,57 Hz, 2 H) 2,59 (s, 3 H) 3,60 (s, 3 H) 7,22 (d, J=8,59 Hz, 1 H) 7,31 (d, J=8,34 Hz, 2 H) 7,57 (d, J=8,34 Hz, 2 H) 7,66 (d, J=8,59 Hz, 1H) 7,97 (dd, J=8,59, 2,53 Hz, 1 H) 8,48 (d, J=2,53 Hz, 1 H) 8,64 (s, 1 H) 8,66 (d, J=8,34 Hz, 1 H);
MS (M+H)+ 484,3.
C. (4-{4-[6-(2-metyl-6-trifluormetyl-pyridin-3-ylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre
(4-{4-[6-(2-metyl-6-trifluormetyl-pyridin-3-ylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre metylester (332 g, 0,69 mmol) ble løst i THF/MeOH (3:1, 4 ml) og til denne ble det tilsatt vandig LiOH (4M, 1 ml). Blandingen ble rørt ved romtemperatur i 18 timer og deretter ble det organiske løsemidlet fjernet med rotasjonsfordampning. Det gjenværende urene produktet ble fortynnet med vann og pH ble justert til 2 med 1M HCl. Det resulterende presipitatet ble samlet opp ved filtrering og tørket under vakuum som ga tittelforbindelsen som et hvitt fast stoff.
<1>H NMR (400 MHz, DMSO-d6) δppm� 0,95 - 1,04 (m, 2 H) 1,44 (dd, J=12,51, 2,91Hz, 2 H) 1,67 (br, s, 1 H) 1,74 - 1,87 (m, 6 H) 2,47 (m, 1 H) 2,60 (s, 3 H) 7,25 (d, J=8,59 Hz, 1 H) 7,30 (d, J=8,34 Hz, 2 H) 7,56 (d, J=8,34 Hz, 2 H) 7,66 (d, J=8,34 Hz, 1 H) 7,97 (dd, J=8,72, 2,65 Hz, 1 H) 8,48 (d, J=2,27 Hz, 1 H) 8,67 (d, J=8,34 Hz, 1 H) 8,80 (s, 1 H);
MS (M+H)+ 470,3.
Eksempel 5-1
(4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre
A. {4-[4-(5-brom-pyridin-2-yl)-fenyl]-cykloheksyl}-eddiksyre metylester
Til en løsning av {4-[4-(4,4,5,5-tetrametyl-[1,3,2]dioksaborolan-2-yl)-fenyl]-cykloheksyl}-eddiksyre metylester (4,0 g, 11,2 mmol, 1,0 ekv.) og 2,5-dibrompyridin (3,2 g, 13,4 mmol, 1,2 ekv.) i 50 ml toluen/etanol (1:1) ble det tilsatt 2M Na2CO3(16,8 ml, 3 ekv.) fulgt av Pd(PPh3)4(0,38 g, 0,34 mmol, 0,03 ekv.). Tofaseblandingen ble overstrømmet med nitrogen i 10 minutter og deretter varmet opp til 60ºC i 3 dager. Reaksjonsblandingen ble avkjølt til romtemperatur og deretter fordelt mellom etylacetat og mettet ammoniumkloridløsning. De organiske ekstraktene ble vasket med saltvann, deretter tørket over natriumsulfat og konsentrert i vakuum. Rensing med silikagelkromatografi (7-40% EtOAc i heksan) ga tittelforbindelsen som et gult faststoff.
<1>H NMR (400 MHz, CDCl3) δ� 1,11 (dd, J=13,01, 2,15 Hz, 2 H) 1,41 – 1,54 (m, 2 H) 1,76 – 1,90 (m, 5 H) 2,20 (d, J=6,57 Hz, 2 H) 2,46 (tt, J=12,09, 3,19 Hz, 1 H) 3,62 (s, 3 H) 7,23 (d, J=8,08 Hz, 2 H) 7,53 (dd, J=8,59, 0,76 Hz, 1 H) 7,77 (dd, J=8,46, 2,40 Hz, 1 H) 7,81 (q, J=3,87 Hz, 1 H) 7,81 (d, J=8,34 Hz, 1 H) 8,64 (d, J=1,77 Hz, 1 H);
(M+H)+ 390,0.
B. (4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester
En mikrobølgebeholder ble tilsatt {4-[4-(5-brom-pyridin-2-yl)-fenyl]-cykloheksyl}-eddiksyre metylester (3,4 g, 8,8 mmol, 1,0 ekv.), 3-amino-6-trifluormetylpyridin (2,1 g, 13,1 mmol, 1,2 ekv.), cesiumkarbonat (7,1 g, 21,9 mmol, 2,5 ekv.), 2-dicykloheksylfosfino-2’,4’,6’-triisopropylbifenyl (X-Phos, 0,42 g, 0,88 mmol, 0,1 ekv.) og palladiumacetat (0,30 g, 0,44 mmol, 0,05 ekv.) i 20 ml toluen/t-butanol (9:1). Suspensjonen ble overstrømmet med nitrogen i 10 minutter og deretter varmet opp til 150ºC under mikrobølgeoppvarming i 45 minutter. Reaksjonsblandingen ble avkjølt til romtemperatur, fordelt mellom etylacetat og vann. De organiske ekstraktene ble vasket med saltvann, tørket deretter over natriumsulfat og konsentrert i vakuum. Rensing med silikagelkromatografi ga tittelforbindelsen.
<1>H NMR (400 MHz, DMSO-d6) δ� 1,10 – 1,21 (m, 1 H) 1,51 (qd, J=12,72, 2,78 Hz, 2 H) 1,70 – 1,87 (m, 5 H) 2,26 (d, J=6,57 Hz, 2 H) 2,50 (m, 1 H) 3,61 (s, 3 H) 7,33 (d, J=8,34 Hz, 2 H) 7,65 (d, J=2,53 Hz, 1 H) 7,67 – 7,74 (m, 2 H) 7,89 (d, J=8,59 Hz, 1 H) 7,95 (d, J=8,34 Hz, 2 H) 8,46 (d, J=2,53 Hz, 1 H) 8,54 (d, J=2,53 Hz, 1 H) 9,18 (s, 1 H);
(M+H)+ 427,3.
C. (4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre
En THF-løsning av (4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester ble behandlet med 10% vandig LiOH og varmet opp til 50ºC over natten. Etter fullstendig reaksjon, ble blandingen surgjort med konsentrert HCl. Det resulterende presipitatet ble isolert ved filtrering som ga tittelforbindelsen.<1>H NMR (400 MHz, DMSO-d6) δ� 1,08 – 1,19 (m, 1 H) 1,14 (dd, J=12,63, 2,27 Hz, 1 H) 1,44 – 1,56 (m, 1H) 1,50 (dd, J=12,51, 2,65 Hz, 1 H) 1,75 (br, S, 1 H) 1,84 (d, J=10,61 Hz, 4 H) 2,14 (d, J=6,82 Hz, 2 H) 2,54 (m, 1 H) 7,33 (d, J=8,34 Hz, 2 H) 7,65 (d, J=2,53 Hz, 1 H) 7,68 – 7,74 (m, 1 H) 7,70 (d, J=8,34 Hz, 1 H) 7,89 (d, J=8,59 Hz, 1 H) 7,95 (d, J=8,59 Hz, 2 H) 8,46 (d, J=2,78 Hz, 1 H) 8,54 (d, J=2,53 Hz, 1 H) 9,20 (s, 1 H);
(M+H)+ 456,3.
Alternativt, kan metylesteren løses i en blanding av THF og vann og behandles med vandig natriumhydroksid (4 ekv.). Blandingen kan deretter røres ved 50ºC i 12 timer, hvorved THF fjernes under redusert trykk som gir en opak hvit slurry, som gir tittelforbindelsen som det korresponderende natriumsaltet etter filtrering.
<1>H NMR (DMSO-d6, 500 MHz) δ10,05 (s, 1 H), 8,59 (d, 1 H, J = 2,8 Hz), 8,54 (s, 1 H), 7,92 (d, 2 H, J = 8,2 Hz), 7,86 (d, 1 H, J = 8,8 Hz), 7,75 (dd, 1 H, J = 8,7, 2,7 Hz), 7,69 (s, 2 H), 7,27 (d, 2 H, J = 8,5 Hz), 2,45 (m, 1 H), 1,84 (m, 4 H), 1,67-1,80 (m, 3 H), 1,41 (m, 2 H), 1,02 (m, 2 H);
MS m/z 456 (M-Na+2H )<+>.
Ved anvendelse av passende aminoderivat kan følgende forbindelser også fremstilles:
Eksempel 5-17
(4-{4-[5-(3-fluor-fenylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre
A. {4-[4-(5-nitro-pyridin-2-yl)-fenyl]-cykloheksyl}-eddiksyre metylester
Til en løsning av 2-brom-5-nitropyridin (0,81 g, 4,0 mmol, 1,0 ekv.) og {4-[4-(4,4,5,5-tetrametyl-[1,3,2]dioksaborolan-2-yl)-fenyl]-cykloheksyl}-eddiksyre metylester (1,5 g, 4,0 mmol, 1,05 ekv.) i 20 ml DME ble det tilsatt 2 ml mettet kaliumkarbonat fulgt av 50 mg Pd(PPh3)4-katalysator. Reaksjonsblandingen ble deretter varmet opp til 80ºC over weekenden. Fjerning av de flyktige forbindelsene i vakuum fulgt av silikagelkromatografi (20% EtOAc i heksan) ga tittelforbindelsen.
1H NMR (400 MHz, DMSO-d6) δppm 0,94 – 1,06 (m, 1 H) 1,00 (dd, J=12,76, 2,15 Hz, 2 H) 1,30 – 1,42 (m, J=12,82, 12,60, 12,60, 2,91 Hz, 2 H) 1,65 (br, S, 2 H) 1,68 (d, J=3,54 Hz, 3 H) 2,11 (d, J=6,82 Hz, 2 H) 3,46 (s, 3 H) 7,27 (d, J=8,34 Hz, 2 H) 7,98 (d, J=8,34 Hz, 2 H) 8,08 (dd, J=8,84, 0,51 Hz, 1 H) 8,47 (dd, J=8,84,2,78 Hz, 1 H) 9,27 (d, J=2,27 Hz, 1 H)
(M+H)+ 355,1.
B. {4-[4-(5-amino-pyridin-2-yl)-fenyl]-cykloheksyl}-eddiksyre metylester
Til en løsning av {4-[4-(5-nitro-pyridin-2-yl)-fenyl]-cykloheksyl}-eddiksyre metylester (1,4 g, 4,0 mmol) i 20 ml EtOH ble det tilsatt Pd/C (0,4 g) fulgt av ammoniumformat (2 g). Reaksjonsblandingen ble varmet opp til refluks i 4 timer og deretter avkjølt til romtemperatur og filtrert gjennom celitt. Fjerning av løsemidlet i vakuum ga tittelforbindelsen.
1H NMR (400 MHz, DMSO-d6) δppm 1,08 – 1,20 (m, 2 H) 1,43 – 1,54 (m, 1 H) 1,48 (dd, J=12,57, 2,46 Hz, 2H) 1,81 (d, J=11,75 Hz, 6 H) 2,26 (d, J=6,69 Hz, 2 H) 3,61 (s, 3 H) 6,98 (dd, J=8,59, 2,78 Hz, 1 H) 7,24 (d, J=8,34 Hz, 2 H) 7,57 (d, J=8,59 Hz, 1 H) 7,81 (d, J=8,34 Hz, 2 H) 8,00 (d, J=2,65 Hz, 1 H);
(M+H)+ 325,2.
C. (4-{4-[5-(3-fluor-fenylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester
Til en løsning av {4-[4-(5-amino-pyridin-2-yl)-fenyl]-cykloheksyl}-eddiksyre metylester (0,10 g, 0,3 mmol, 1,0 ekv.) og 3-fluorfenylborsyre (0,086 g, 0,61 mmol, 2,0 ekv.) i 5 ml diklormetan ble det tilsatt pyridin (0,05 ml, 0,61 mmol, 2,0 ekv.), kobber(II)acetat (0,084 g, 0,46 mmol, 1,5 ekv.) og 4Å molekylsikt. Den heterogene blandingen ble rørt åpen for atmosfære i 18 timer. Rensing med silikagelkromatografi (20-45% EtOAc i heksan) ga tittelforbindelsen.
1H NMR (400 MHz, DMSO-d6) δppm 1,12 – 1,27 (m, 2 H) 1,47 (br, S, 1 H) 1,53 (dd, J=12,51, 2,65 Hz, 1 H) 1,67 (br, S, 1 H) 1,85 (d, J=12,38 Hz, 4 H) 2,29 (d, J=6,57 Hz, 2 H) 3,34 (s, 2 H) 3,64 (s, 3 H) 6,69 (td, J=8,46, 2,53 Hz, 1 H) 6,89 (dt, J=11,62, 2,15 Hz, 1 H) 6,96 (dd, J=7,83, 1,77 Hz, 1 H) 7,33 (d, J=8,34 Hz, 2H) 7,63 (dd, J=8,59, 2,78 Hz, 1 H) 7,84 (d, J=8,59 Hz, 1 H) 7,95 (d, J=8,34 Hz, 2 H) 8,47 (s, 1 H) 8,71 (s, 1H);
(M+H)+ 419,3.
D. (4-{4-[5-(3-fluor-fenylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre Til en løsning av (4-{4-[5-(3-fluor-fenylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester (0,10 g) i 5 ml THF ble det tilsatt 5ml av en 4M LiOH-løsning. Reaksjonsblandingen ble rørt over natten ved romtemperatur og deretter varmet opp til 60ºC over natten. Surgjøring til pH 1 ved anvendelse av konsentrert HCl ga et presipitat som ble filtrert som ga tittelforbindelsen.
1H NMR (400 MHz, DMSO-d6) δppm 0,95 – 1,12 (m, 1 H) 1,02 (dd, J=11,62, 9,35 Hz, 2 H) 1,33 (br, S, 1 H) 1,38 (dd, J=12,51, 2,65 Hz, 2 H) 1,62 (d, J=9,35 Hz, 2 H) 1,71 (d, J=10,11 Hz, 4 H) 2,03 (d, J=6,82 Hz, 2 H) 6,64 – 6,73 (m, 1 H) 6,86 – 6,93 (m, 2 H) 7,29 (d, J=8,34 Hz, 2 H) 7,21 – 7,35 (m, 1 H) 7,78 (d, J=8,34 Hz, 2H) 7,83 – 7,89 (m, 1 H) 7,89 – 7,97 (m, 1 H) 8,30 (s, 1 H) 9,26 (br, S, 1 H);
(M+H)+ 405,1.
Følgende forbindelser kan fremstilles på analog måte:
Eksempel 5-23
(4-{4-[5-(benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre
A. (4-{4-[5-(benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester
65 mg {4-[4-(5-amino-pyridin-2-yl)-fenyl]-cykloheksyl}-eddiksyre metylester og 0,3 ml 2-klorbenzoksazol ble løst i 1,5 ml t-BuOH/DME (1:1) i et 5 ml mikrobølgerør med en rørestav.0,1 ml 4N-HCl i dioksan ble tilsatt og reaksjonskaret ble forseglet og varmet opp til 120ºC i 2 timer med mikrobølgebestråling. Reaksjonsblandingen ble fortynnet med etylacetat og de resulterende presipitatene ble filtrert og vasket med etylacetat. Filterkaken ble tørket med luft i sugtrakten og analysert med 1H-NMR (400 MHz, DMSO-d6) d ppm 1,2 (s, 3 H) 1,5 (s, 2 H) 1,8 (s, 6 H) 2,3� (d, J=6,8 Hz, 2 H) 3,6 (s, 4 H) 7,2 (m, 1 H) 7,3 (m, 1 H) 7,3 (d, J=8,3 Hz, 2 H) 7,5 (d, J=13,9 Hz, 2 H) 8,0 (m, 3 H) 8,4 (m, 1 H) 8,9 (d, J=2,3 Hz, 1 H) 11,0 (s, 1 H);
(M+H)+ 442,2.
B. (4-{4-[5-(benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre (4-{4-[5-(benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester ble rørt i 4 ml THF/vann (1:1) og behandlet med 30 mg LiOH ved omgivelsestemperatur. Reaksjonsblandingen ble deretter varmet opp til 50ºC og rørt over natten. LC-MS-analyse indikerte at reaksjonen var fullstendig. Reaksjonsblandingen ble fortynnet med vann (2 ml) og nøytralisert med 6N HCl. Det resulterende presipitatet ble filtrert og vasket med vann og etylacetat. Presipitatet ble tørket og analysert med 1H NMR (400 MHz, DMSO-D6) d� ppm 1,1 (m, 2 H) 1,5 (s, 2 H) 1,8 (t, J=6,7 Hz, 1 H) 1,8 (s, 4 H) 2,2 (d, J=6,8 Hz, 2 H) 7,2 (td, J=7,8, 1,3 Hz, 1H) 7,3 (td, J=7,6, 1,1 Hz, 1 H) 7,3 (d, J=8,3 Hz, 2 H) 7,5 (dd, J=13,9, 7,3 Hz, 2 H) 8,0 (d, J=8,1 Hz, 3 H) 8,3 (dd, J=8,7, 2,7 Hz, 1 H) 8,9 (d, J=3,0 Hz, 1 H);
(M+H)+ 428,1.
Alternativt, kan metylesteren løses i THF og behandles med vandig natriumhydroksid (4 ekv.). Blandingen kan deretter røres ved 50ºC i 12 timer, hvorved vann kan tilsettes og det meste av det organiske løsemidlet kan fjernes under redusert trykk. Tilsetning av acetonitril fulgt av avkjøling kan gi et presipitat som kan isoleres ved filtrering for å gi tittelforbindelsen som det korresponderende natriumsaltet.
<1>H NMR (DMSO-d6, 500 MHz) δ8,73 (s, 1 H), 8,29 (dd, 1 H, J = 8,7, 2,7 Hz), 7,86 (d, 2 H, J = 8,2 Hz), 7,81 (d, 1 H, J = 8,8 Hz), 7,31 (m, 2 H), 7,21 (d, 2 H, J = 8,2 Hz), 7,09 (t, 1 H, J = 7,6 Hz), 6,97 (t, 1 H, J = 7,7 Hz), 2,40 (m, 1 H), 1,83 (d, 2 H, J = 6,9 Hz), 1,75 (m, 4 H), 1,65 (m, 1 H), 1,40 (m, 2 H), 1,02 (m, 2 H);
MS m/z 428 (M-Na+2H )<+>.
Ved anvendelse av fremgangsmåter analoge med de som er beskrevet ovenfor, kan følgende forbindelser også fremstilles:
Eksempel 6-1
(4-{4-[6-(3-klor-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre
A. [4-(4-acetyl-fenyl)-cykloheksyl]-eddiksyre etylester
Til en 0ºC løsning av (4-fenyl-cykloheksyl)-eddiksyre etylester (15 g, 61 mmol, 1,0 ekv.) i 200 ml DCM ble det tilsatt aluminiumtriklorid (16 g, 122 mmol, 2,0 ekv.) porsjonsvis i løpet av 15 minutter. Acetylklorid (4,7 ml, 67 mmol, 1,10 ekv.) ble deretter dråpevis tilsatt via sprøyte. Den homogene løsningen ble rørt ved 0ºC i 2 timer og deretter ble reaksjonen forsiktig stoppet med 300 ml isvann. Blandingen ble ekstrahert med DCM (3 x 150 ml) og de organiske ekstraktene ble vasket med mettet bikarbonat og saltvannløsning. Fjerning av løsemidlet i vakuum ga tittelforbindelsen.
<1>H NMR (400 MHz, kloroform-d) δppm 1,10 (q, J=11,96 Hz, 2 H) 1,20 (t, J=7,20 Hz, 3 H) 1,40 – 1,51 (m, 2 H) 1,84 (d, J=11,12 Hz, 4 H) 1,76 – 1,87 (m, 1 H) 2,17 (d, J=6,82 Hz, 2 H) 2,50 (s, 3 H) 4,07 (q, J=7,07 Hz, 2 H) 7,22 (d, J=8,34 Hz, 2 H) 7,81 (d, J=8,08 Hz, 2 H);
(M+H)+ 289,1.
B. {4-[4-(6-okso-1,6-dihydro-pyridazin-3-yl)-fenyl]-cykloheksyl}-eddiksyre etylester
Til en løsning av [4-(4-acetyl-fenyl)-cykloheksyl]-eddiksyre etylester (17 g, 59 mmol, 1,0 ekv.) i 100 ml iseddiksyre ble det tilsatt glyoksylsyre monohydrat (5,4 g, 59 mmol, 1,0 ekv.) som et faststoff. Løsningen ble varmet opp til 100ºC i 2 timer. Blandingen ble deretter avkjølt til 40ºC og deretter ble 75 ml vann tilsatt fulgt av 120 ml av en 28% ammoniumhydroksidløsning til pH ble målt til å være 8. Hydrazin (2,0 ml, 65 mmol, 1,1 ekv.) ble deretter tilsatt via sprøyte og reaksjonsblandingen ble varmet opp til 95ºC i 2 timer. Etter avkjøling til romtemperatur ble det faste presipitatet filtrert fra som ga tittelforbindelsen i tillegg til det ikke-eliminerte produktet {4-[4-(5-hydroksy-6-okso-1,4,5,6-tetrahydro-pyrazin-3-yl)-fenyl]-cykloheksyl}-eddiksyre etylester. Denne blandingen ble tatt med til neste trinn uten ytterligere rensing.
(M+H)+ 341,2.
C. {4-[4-(6-klor-pyridazin-3-yl)-fenyl]-cykloheksyl}-eddiksyre etylester
En 50 ml kolbe ble tilsatt {4-[4-(6-okso-1,6-dihydro-pyridazin-3-yl)-fenyl]-cykloheksyl}-eddiksyre etylester (0,76 g, 2,2 mmol, 1,0 ekv.) i 20 ml toluen fulgt av fosforoksyklorid (0,62 ml, 6,7 mmol, 3,0 ekv.). Suspensjonen ble varmet opp til 100ºC, hvorved en homogen løsningen fremkom. Reaksjonsblandingen ble rørt over natten ved 100ºC og deretter avkjølt til romtemperatur. Fjerning av de flyktige forbindelsene i vakuum ga tittelforbindelsen.
1H NMR (400 MHz, kloroform-d) δppm 1,07 – 1,17 (m, 2 H) 1,20 (t, J=7,07 Hz, 3 H) 1,43 – 1,53 (m, 2 H) 1,78 – 1,90 (m, 5 H) 2,18 (d, J=6,57 Hz, 2 H) 2,44 – 2,52 (m, 1 H) 4,08 (q, J=7,07 Hz, 2 H) 7,29 (d, J=8,34 Hz, 2 H) 7,46 (d, J=9,09 Hz, 1 H) 7,72 (d, J=9,09 Hz, 1 H) 7,90 (d, J=8,59 Hz, 2 H); ̈
(M+H)+ 359.
D. (4-{4-[6-(3-klor-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre etylester
Til en suspensjon av {4-[4-(6-klor-pyridazin-3-yl)-fenyl]-cykloheksyl}-eddiksyre etylester (2,0 g, 5,6 mmol, 1,0 ekv.) i 40 ml dioksan ble det tilsatt 3-kloranilin (0,70 ml, 6,7 mmol, 1,2 ekv.) fulgt av 2ml 4N HCl i dioksan. Blandingen ble deretter varmet opp til 100ºC over natten. Reaksjonsblandingen ble fordelt mellom EtOAc og mettet bikarbonatløsning og de organiske ekstraktene ble deretter vasket med saltvann og tørket. Fjerning av løsemidlet i vakuum ga tittelforbindelsen.
1H NMR (400 MHz, kloroform-d) δppm 1,07 – 1,17 (m, 2 H) 1,21 (t, J=7,20 Hz, 3 H) 1,42 – 1,53 (m, 2 H) 1,86 (t, J=10,99 Hz, 4 H) 1,78 – 1,90 (m, 1 H) 2,18 (d, J=6,57 Hz, 2H) 2,47 (td, J=12,00, 3,03 Hz, 1 H) 4,08 (q, J=7,24 Hz, 2 H) 7,03 (d, J=7,58 Hz, 1 H) 7,26 (d, J=8,08 Hz, 3 H) 7,20 – 7,28 (m, 2 H) 7,45 (s, 1 H) 7,68 (d, J=9,35 Hz, 1 H) 7,84 (d, J=8,34 Hz, 2 H);
(M+H)+ 450,2.
E. 4-{4-[6-(3-klor-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre Til en løsning av (4-{4-[6-(3-klor-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre etylester (1,8 g) i 50 ml THF/EtOH (4:1) ble det tilsatt 5 ml 10% LiOH. Reaksjonsblandingen ble rørt ved 50ºC i 3 timer og deretter rørt over natten ved romtemperatur. Surgjøring med konsentrert HCl ga et presipitat som ble rekrystallisert fra EtOH som ga tittelforbindelsen.
1H NMR (400 MHz, DMSO-d6) δppm 1,00 – 1,10 (m, 2 H) 1,37 – 1,48 (m, 2 H) 1,61 – 1,71 (m, 1H) 1,76 (d, J=11,12 Hz, 4 H) 2,05 (d, J=6,82 Hz, 2 H) 6,92 (ddd, J=7,83, 2,02, 0,76 Hz, 1 H) 7,14 (d, J=9,60 Hz, 1 H) 7,28 (dd, J=8,21, 6,44 Hz, 3 H) 7,49 (ddd, J=8,34, 2,02, 0,76 Hz, 1 H) 7,91 (dd, J=16,55, 8,97 Hz, 3H) 8,10 (t, J=2,02 Hz, 1 H) 9,52 (s, 1 H);
(M+H)+ 422,2.
Alternativt, kan metylesteren løses i THF og behandles med vandig natriumhydroksid (4 ekv.). Blandingen kan deretter røres ved 50ºC i 12 timer, hvorved vann kan tilsettes og det meste av det organiske løsemidlet kan fjernes under redusert trykk. Tilsetning av acetonitril fulgt av avkjøling kan gi et presipitat som kan isoleres ved filtrering som gir tittelforbindelsen som det korresponderende natriumsaltet.
Ved anvendelse av passende amin, kan følgende forbindelser også fremstilles på tilsvarende måte:
Eksempel 7
(4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyrazin-2-yl]-fenyl}-cykloheksyl)-eddiksyre
A. Pyrazin-2-yl-(6-trifluormetyl-pyridin-3-yl)-amin
Til en løsning av 5-amino-2-trifluormetylpyridin (0,81 g) i 3 ml toluen, ble det tilsatt klorpyrazin (0,45 ml, 1,0 ekv.) via sprøyte. Den homogene løsningen ble varmet opp til 95ºC og deretter avkjølt til romtemperatur og konsentrert i vakuum. Rensing med silikagelkromatografi (40% EtOAc i heksan) ga tittelforbindelsen.
1H NMR (400 MHz, kloroform-D) δppm 7,5 (s, 1 H) 7,6 (s, 1 H) 8,0 (s, 1 H) 8,2 (s, 1 H) 8,4 (s, 2 H) 8,8 (s, 1 H);
(M+H)+ 241,1.
B. (5-brom-pyrazin-2-yl)-(6-trifluormetyl-pyridin-3-yl)-amin
En løsning av pyrazin-2-yl-(6-trifluormetyl-pyridin-3-yl)-amin (0,47 g) ble løst i 50 ml MeOH og ble deretter tilsatt en N-bromsuksinimid (0,35 g) i en enkel porsjon som et faststoff. Reaksjonsblandingen ble rørt over natten ved romtemperatur og deretter konsentrert i vakuum. Rensing med silikagelkromatografi (25% EtOAc i heksan) ga tittelforbindelsen.
1H NMR (400 MHz, kloroform-D) δppm 6,7 (s, 1 H) 7,5 (s, 1 H) 7,9 (s, 1 H) 8,2 (s, 2 H) 8,6 (s, 1 H);
(M+H)+ 320,9.
C. (4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyrazin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester
En løsning av (5-brom-pyrazin-2-yl)-(6-trifluormetyl-pyridin-3-yl)-amin (0,072 g) og {4-[4-(5-brom-pyridin-2-yl)-fenyl]-cykloheksyl}-eddiksyre metylester (0,087 g) i 2 ml DME ble tilsatt 2M natriumkarbonat (1 ml) og Pd(PPh3)4(0,027 g, 0,1 ekv.). Tofaseblandingen ble overstrømmet med nitrogen i 3 minutter og deretter rørt ved 130ºC under mikrobølgeoppvarming i 30 minutter. Reaksjonsblandingen ble fordelt mellom EtOAc og vann og de organiske ekstraktene ble tørket over magnesiumsulfat og konsentrert i vakuum. Rensing med silikagelkromatografi (33% EtOAc i heksan) ga tittelforbindelsen.
(M+H)+ 471,2.
D. (4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyrazin-2-yl]-fenyl}-cykloheksyl)-eddiksyre
Til en løsning av (4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyrazin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester (0,051 g) i 4 ml THF/vann (1:1) ble det tilsatt fast litiumhydroksid (0,030 g). Reaksjonsblandingen ble rørt ved romtemperatur i 48 timer og deretter varmet opp til 45ºC i 24 timer. Reaksjonsblandingen ble nøytralisert med 6N saltsyre og deretter renset med omvendtfase preparativ HPLC som ga tittelforbindelsen.
1H NMR (400 MHz, DMSO-D6) δppm 1,1 (s, 2 H) 1,3 (s, 1 H) 1,6 (s, 2 H) 1,9 (s, 6 H) 3,5 (s, 6 H) 7,4 (s, 2 H) 7,9 (s, 1 H) 8,0 (s, 2 H) 8,6 (s, 1 H), 8,6 (s, 1 H) 8,9 (s, 1 H) 9,1 (s, 1 H) 10,9 (s, 1 H);
(M+H)+ 457,1.
Alternativt kan metylesteren løses i THF og behandles med vandig natriumhydroksid (4 ekv.). Blandingen kan deretter røres ved 50ºC i 12 timer, hvorved vann kan tilsettes og det meste av det organiske løsemidlet kan fjernes under redusert trykk. Tilsetning av acetonitril fulgt av avkjøling, kan gi et presipitat som kan isoleres ved filtrering som gir tittelforbindelsen som det korresponderende natriumsaltet.
Claims (18)
- Patentkrav 1. Forbindelse, k a r a k t e r i s e r t v e d formelen:hvori: - B er valgt fra gruppen som består av pyridin, pyridazin, pyrazin og oksazol; - -L1er -NH-; - A er valgt fra fenyl, pyridin og benzoksazol, hvori bestanddelen A er usubstituert eller substituert med 1 til 2 substituenter uavhengig valgt fra klor, metyl, metoksy, trifluormetyl og cyano; - -L2er –CH2-; - E er valgt fra gruppen som består av –COOH, -COOCH3og –COOCH2CH3; eller et farmasøytisk akseptabelt salt derav, stereoisomerer, krystallinske former eller polymorfer derav.
- 2. Forbindelse, k a r a k t e r i s e r t v e d formelen:hvori: - B er valgt fra gruppen som består av pyridin, pyridazin, pyrazin og oksazol; - -L1er -NH-; - A er valgt fra fenyl, pyridin og benzoksazol, hvori bestanddelen A er usubstituert eller substituert med 1 til 2 substituenter uavhengig valgt fra klor, metyl, metoksy, trifluormetyl og cyano; - -L2er –CH2-; - E er valgt fra gruppen som består av –COOH, -COOCH3og –COOCH2CH3; eller et farmasøytisk akseptabelt salt derav, stereoisomerer, krystallinske former eller polymorfer derav.
- 3. Forbindelse, k a r a k t e r i s e r t v e d formel I:hvori - A er valgt fra fenyl, pyridin og benzoksazol, hvori bestanddelen A er usubstituert eller substituert med 1 til 2 substituenter uavhengig valgt fra klor, metyl, metoksy, trifluormetyl og cyano; - E’ er -L2-E; - -L2er –CH2-; - E er valgt fra gruppen som består av –COOH, -COOCH3og –COOCH2CH3; eller farmasøytisk akseptable salter, stereoisomerer, krystallinske former eller polymorfer derav.
- 4. Forbindelse, k a r a k t e r i s e r t v e d formel II:hvori: - A er fenyl, pyridin eller benzoksazol, hvori bestanddelen A eventuelt er substituert med klor, metyl, metoksy eller trifluormetyl; - E’ er -L2-E; - L2er –CH2-; - E er valgt fra gruppen som består av –COOH, -COOCH3og –COOCH2CH3; eller farmasøytisk akseptable salter, stereoisomerer, krystallinske former eller polymorfer derav.
- 5. Forbindelse ifølge krav 3 eller 4, k a r a k t e r i s e r t v e d at E’ er -CH2-C(O)OH, eller et farmasøytisk akseptabelt salt derav.
- 6. Forbindelse ifølge krav 1, k a r a k t e r i s e r t v e d at den er valgt fra gruppen som består av: (4-{4'-[2-(3-klor-fenylamino)-oksazol-5-yl]-bifenyl-4-yl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-klor-fenylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-metylfenylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-trifluormetylfenylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-metoksyfenylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(2-metoksyfenylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(pyridin-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, {4-[4-(5-fenylaminopyridin-2-yl)-fenyl]-cykloheksyl}-eddiksyre, (4-{4-[5-(5-cyanopyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(5-trifluormetylpyridin-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(4-trifluormetylfenylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(5-metylpyridin-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(5-trifluormetylpyridin-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester, (4-{4-[5-(5-klorpyridin-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(6-metoksypyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(3-klor-fenylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-klor-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, {4-[4-(6-m-tolylamino-pyridazin-3-yl)-fenyl]-cykloheksyl}-eddiksyre, (4-{4-[6-(3-trifluormetyl-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-metoksy-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-cyano-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(4-klor-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, {4-[4-(6-p-tolylamino-pyridazin-3-yl)-fenyl]-cykloheksyl}-eddiksyre, (4-{4-[6-(4-trifluormetyl-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-klor-4-metoksy-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-klor-2-metyl-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, {4-[4-(6-fenylamino-pyridazin-3-yl)-fenyl]-cykloheksyl}-eddiksyre, (4-{4-[6-(3-klor-2-metoksy-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(2-metoksy-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(4-metoksy-fenylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(6-trifluormetyl-pyridin-3-ylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(2-metyl-6-trifluormetyl-pyridin-3-ylamino)-pyridazin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[6-(3-klor-2-metoksy-fenylamino)-pyridazin-3-yl]-fenyl}cykloheksyl)-eddiksyre, (4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyrazin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(6-trifluormetyl-pyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester, (4-{4-[5-(5-klor-6-metoksy-pyridin-3-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(3-klor-5-metyl-pyridin-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(6-metyl-benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(6-klor-benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre metylester, (4-{4-[5-(6-klor-benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, (4-{4-[5-(5-klor-6-metoksy-benzoksazol-2-ylamino)-pyridin-2-yl]-fenyl}-cykloheksyl)-eddiksyre, og (4-{4-[6-(2-metyl-6-trifluormetyl-pyridin-3-ylamino)-pyridin-3-yl]-fenyl}-cykloheksyl)-eddiksyre, eller et farmasøytisk akseptabelt salt derav.
- 7. Forbindelse ifølge krav 1, k a r a k t e r i s e r t v e d at den er:eller et farmasøytisk akseptabelt salt derav.
- 8. Forbindelse ifølge krav 7, k a r a k t e r i s e r t v e d at den er på natriumsalt form.
- 9. Forbindelse ifølge krav 1, k a r a k t e r i s e r t v e d at den er:eller et farmasøytisk akseptabelt salt derav.
- 10. Farmasøytisk sammensetning, k a r a k t e r i s e r t v e d at den innbefatter forbindelsen ifølge et hvilket som helst av kravene 1-9, og en farmasøytisk akseptabel bærer eller eksipient.
- 11. Farmasøytisk kombinasjon, k a r a k t e r i s e r t v e d at den innbefatter: i) en forbindelse ifølge et hvilket som helst av kravene 1-9, og ii) minst en forbindelse valgt fra a) antidiabetiske midler, b) hypolipidemiske midler, c) antifedmemidler, d) antihypertensive midler, e) agonister av peroksisomproliferatoraktivatorreseptorer.
- 12. Farmasøytisk kombinasjon ifølge krav 11, k a r a k t e r i s e r t v e d at den er en fiksert kombinasjon eller en fri kombinasjon.
- 13. Farmasøytisk sammensetning, k a r a k t e r i s e r t v e d at den innbefatter i) en forbindelse ifølge et hvilket som helst av kravene 1-9, ii) minst en forbindelse valgt fra a) antidiabetiske midler, b) hypolipidemiske midler, c) antifedmemidler, d) antihypertensive midler, e) agonister av peroksisomproliferatoraktivatorreseptorer, og iii) en eller flere farmasøytisk akseptable bærere.
- 14. Farmasøytisk kombinasjon ifølge krav 11 eller 12, for behandling av insulinresistens, glukoseintoleranse, type 2 diabetes, fedme, hypertensjon, iskemiske sykdommer i store og små blodkar, dyslipidemi, aterosklerose, vaskulær restenose, irritabelt tarmsyndrom, pankreatitt, kreft, osteoporose, muskelskjelett, neurodegenerative sykdommer, infeksjonssykdommer og sykdommer som involverer inflammasjon og immunsystemet.
- 15. Farmasøytisk kombinasjon ifølge krav 11 eller 12 for behandling eller forebygging av tilstander eller forstyrrelser assosiert med DGAT1-aktivitet.
- 16. Forbindelse ifølge et hvilket som helst av kravene 1-9 for behandling eller forebygging av tilstander eller forstyrrelser assosiert med DGAT1-aktivitet.
- 17. Forbindelse ifølge krav 16, der forstyrrelsen er valgt fra metabolittiske forstyrrelser slike som fedme, diabetes, anorexia nervosa, bulimi, kakesi, syndrom X, insulinresistens, hypoglykemi, hyperglykemi, hyperurisemi, hyperinsulinemi, hyperkolesterolemi, hyperlipidemi, dyslipidemi, blandet dyslipidemi, hypertriglyseridemi og ikke-alkoholfettleversykdom; kardiovaskulære sykdommer, slike som aterosklerose, arteriosklerose, akutt hjertesvikt, kongestiv hjertesvikt, koronar arteriesykdom, kardiomyopati, myokardisk infarkt, angina pektoris, hypertensjon, hypotensjon, slag, iskemi, iskemisk reperfusjonsskade, aneurisme, restenose og vaskulær stennose; neoplastiske sykdommer, slike som faste tumorer, hudkreft, melanom, lymfom og endotelialkreft, f.eks. brystkreft, lungekreft, kolorektal kreft, magekreft, andre kreftformer i gastrointestinaltrakten (f.eks. spiserørkreft og bukspyttkjertelkreft), prostatakreft, nyrekreft, leverkreft, blærekreft, cervikalkreft, livmorkreft, testikkelkreft og eggstokkreft; dermatologiske tilstander slike som acne vulgaris, og anoreksi.
- 18. Forbindelse ifølge krav 16, der forstyrrelsen er valgt fra en metabolittisk forstyrrelse slik som fedme, diabetes eller hyperlipidemi.
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US78785906P | 2006-03-31 | 2006-03-31 | |
PCT/US2007/007772 WO2007126957A2 (en) | 2006-03-31 | 2007-03-28 | New compounds |
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