NO329290B1 - Forbindelser for behandling av antraks og inhibering av letal faktor - Google Patents
Forbindelser for behandling av antraks og inhibering av letal faktor Download PDFInfo
- Publication number
- NO329290B1 NO329290B1 NO20045630A NO20045630A NO329290B1 NO 329290 B1 NO329290 B1 NO 329290B1 NO 20045630 A NO20045630 A NO 20045630A NO 20045630 A NO20045630 A NO 20045630A NO 329290 B1 NO329290 B1 NO 329290B1
- Authority
- NO
- Norway
- Prior art keywords
- amino
- fluoro
- methylphenylsulfonyl
- hydroxy
- mmol
- Prior art date
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Classifications
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/31—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
- C07C311/32—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
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- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
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Abstract
Oppfinnelsen angår forbindelser med formel (I), og en fremgangsmåte for behandling av antraks eller inhibering av letal faktor ved å administrere et preparat som inneholder en forbindelse med formel (I) og en farmasøytisk akseptabel bærer. Det beskrives også anvendelse av forbindelsene med formel (I) for å behandle andre tilstander beslektet med en antraksinfeksjon.
Description
Bakgrunn for oppfinnelsen
Antraks er en bakterieinfeksjon dannet av Bacillus anthracis. Bacillus anthracis- endosporer kan komme inn i kroppen gjennom hudavskrapninger, inhalering eller fordøyelse. Bacillus anthracis produserer et antrakstoksin som ofte er dødelig (Dixon et al. (1999), N. Engl. J. Med. 341, 815-26.)
Antrakstoksin består av tre proteiner, en reseptor-bindende komponent betegnet beskyttende antigen og to enzymat-iske komponenter kalt ødemfaktor og letal faktor ("LF") (Mock et al. (2001), Annu. Rev. Microbiol., 55, 647-71). Letal faktor er en sinkavhengig metallprotease som synes å utøve toksiske virkninger ved å spalte mitogenaktiverte proteinkinasekinaser (MKK) (Vitale et al. (1998), Biochem. Biophys. Res. Commun., 248, 706-11; Vitale et al. (2000), Biochem. J., 352, Pt 3, 739-45; Duesbery et al. (1998), Science, 280, 734-7; Duesbery et al., WO 99/50439.
Vitale og medarbeidere har anvendt mikrosekvensering for å identifisere det stedet i forskjellige MKK som spaltes av den letale faktor (se tabell 1, Vitale et al. (2000), Biochem. J., 352 Pt 3, 739-45.). Letalfaktorens spalting av forskjellige MKK skjedde inne i N-terminalområdet foran kinasedomenet. Inn-retting av sekvensene som flankerer spaltingsstedet, avslørte noen konsensusmotiver: et hydrofobt residu i stilling P2 og Pl<1>, og minst ett basisk residu mellom P4 og P7 (Vitale et al.
(2000), Biochem. J., 352, Pt 3, 739-45).
Det er vist at den letale faktor spalter syntetiske peptider in vitro (Hammond et al. (1998), Infect. Immun., 66, 2374-8). Spalting in vitro ble inhibert med 1,10-fenantrolin eller 10 mM EDTA, som begge danner komplekser med sink.
Bacillus anthracis er en spordannende grampositiv basill som er det etiologiske middel for antraks. Antraks er en sykdom som kan finnes globalt i tempererte soner (f.eks. Sør- og sentral-Amerika, Sør- og Øst-Europa, Asia, Afrika, Midtøsten og Karibia) og overføres til mennesker gjennom håndtering eller konsumpsjon av kontaminerte animalske produkter (f.eks. ved å spise utilstrekkelig varmebehandlet kjøtt av infiserte dyr). Ville pattedyr som hjortedyr, gnu og elefanter, og husdyr som geit, sau, storfe, hest og svin har høy risiko for å få sykdommen. Generelt får de sykdommen gjennom beiting på kontaminerte jorder, ved å ete kontaminert for eller drikke av kontaminerte vannhull. Sporer av Bacillus anthracis kan forbli levedyktige i jordsmonnet i mange år. Se Helgason et al., Applied and Environ-mental Microbiology, 2000, 55(6), s. 2627-2630; Wber et al., Antimicrob. Agents and Chemotherapy, 1988, 32(5):642-645; og Doganay et al., Scand. J. Inf. Dis., 1991, 23:333-335, for videre diskusjon om Bacillus anthracis.
Hos mennesker kan det forekomme tre former av antraks-infeksjoner, kutant, gastrointestinalt og ved inhalering. Med den kutane formen skjer infeksjoner når bakterier eller sporer kommer inn i et sår eller en avskrapning på huden. Se Synder, J.W., Shapiro, D.S., Gilchrist, M.J.R. et al., "Basic Diagnostic Testing Protocols for Level A Laboratories (For The Presumptive Indentification of Bacillus anthracis)" på www.ban.asm.la.cp.102401f, 24. oktober 2001, s.1-20; og Dixon et al., NEJM, 341:815-826, 9. september 1999, nr. 11. Symptomer på hudinfeksjon er generelt hevelser som klør eller hevelser som ligner på insektbitt. I løpet av 1-2 døgn vil hevelsene eller hevelsen utvikle seg til en væskefylt blære som revner og danner et smertefritt sår med et karakteristisk svart, nekrotisk (døende) område i midten. Dersom det forblir ubehandlet, kan det resultere i død, men imidlertid er dødsfall sjelden dersom det administreres en hensiktsmessig antibiotikabehandling.
Gastrointestinal antraks forekommer generelt ved konsumpsjon av kjøtt som er kontaminert med bakterien. Dette resulterer i en akutt inflammasjon i fordøyelseskanalen. Symptomer som kvalme, tap av appetitt, oppkast, feber, samt magesmerter, oppkast av blod og alvorlig diaré er indikasjoner på gastrointestinal antraks. For denne form av human antraks er dødelighetsraten anslått å være 25-60 %.
Inhalering av antraks er mest sannsynlig resultatet av overlagt utslipp av aerosol med Bacillus anthracis, slik som ved en bioterrorismehandling. Denne form for human antraksinfeksjon har vanligvis en inkubasjonsperiode på 1-6 døgn, hvor de første signaler er feber, ubehag, tretthet, uproduktiv hoste og/eller svakt ubehag i brystet. Disse første symptomer følges ofte av en kort periode med bedring, fulgt av en plutselig utvikling av alvorlig åndenød med tungpustenhet, svette og blåfarget hud. Død skjer vanligvis innen 24-36 timer etter at åndenød har startet, på tross av aggressiv behandling.
De fleste Bacillus anthracis-stammer er følsomme for en lang rekke antibiotika. De vanligst foreskrevne terapier i dag er ciprofloxacin, penicillin eller doksysyklin. Imidlertid er disse midlenes virknings- og bivirkningsprofiler ikke ideelle.
Selv om antibiotika kan drepe bakterien som forårsaker antraks, vil det tredelte antrakstoksin fortsette å skade kroppen selv etter at selve bakterien er død. Det er derfor fortsatt behov for nye og effektive terapier med forbedret virkning, med få eller ingen bivirkninger og som inhiberer den skjærende evne som den letale faktor har til å kutte i stykker viktige vertsmolekyler.
Sammenfatning av oppfinnelsen
Denne oppfinnelse angår forbindelsene listet opp i krav 1, og farmasøytisk akseptable salter, enantiomerer, diastereomerer og blandinger derav.
Oppfinnelsen angår også et farmasøytisk preparat som omfatter en forbindelse ifølge oppfinnelsen, og en farmasøytisk akseptabel bærer.
Denne oppfinnelsen angår videre anvendelse av forbindelsene ifølge oppfinnelsen for tilvirkning av et medikament for å inhibere aktiviteten av letal faktor (LF) frigjort fra bakterier i et patterdyr.
Dette og andre aspekter ved oppfinnelsen vil forstås ved granskning av oppfinnelsen i sin helhet.
Nærmere beskrivelse av oppfinnelsen
Den foreliggende oppfinnelse er rettet på forbindelsene angitt i krav 1, som er egnet for behandling av antraks eller inhibering av letal faktor ved å administrere, fortrinnsvis intravenøst eller intramuskulært, en blanding som inneholder en forbindelse ifølge krav 1, og en farmasøytisk akseptabel bærer.
Oppfinnelsen er detaljert beskrevet her ved å anvende begrepene definert nedenfor, så sant annet ikke er spesifisert.
En annen utførelsesform av denne oppfinnelse angår et farmasøytisk preparat som omfatter en forbindelse ifølge krav 1 og en farmasøytisk akseptabel bærer.
En annen utførelsesform av denne oppfinnelse angår anvendelse av en forbindelse ifølge krav 1 for tilvirkning av et medikament for behandling eller profylakse av antraks og beslek-tede tilstander. Enda en utførelsesform innebærer anvendelse av en forbindelse med formel I for produksjon av et medikament for å inhibere letal faktor.
Forbindelsene ifølge krav 1 kan kombineres med ett eller flere kjente legemidler valgt blant klinisk anvendelige, bakteriedrepende midler (f.eks. andre beta-laktamer eller aminoglykosider), inhibitorer av beta-laktamase, renale tubulære blokkeringsmidler (f.eks. probenecid) og inhibitorer av meta-boliserende enzymer (f.eks. inhibitorer av dehydropeptidaser, f.eks. Z-2-acylamino-3-substituerte propenoater som cilastatin) og N-acylerte aminosyrer (se f.eks. EP-A-178911) som reduserer uheldige virkninger på nyrene. Eksempler på legemidler som kan kombineres med forbindelsene med formel I er imipenem, meropenem, vankomycin, cilastatin, cefoksitin, penicillin, klavulansyre, probenecid, tetrasyklin, ciprofloxacin, norfloxacin eller en blanding derav. Det foretrekkes at når imipenem anvendes som et legemiddel, anvendes det i kombinasjon med cilastatin (denne kombinasjon er markedsført som "PRIMAXIN").
Egnede farmasøytisk akseptable salter av forbindelsene anvendt i denne oppfinnelse, innbefatter syreaddisjonssalter, slik som hydrogenklorid, hydrogenbromid, sitrat, maleat og salter dannet med fosforsyre og svovelsyre. I et annet aspekt er egnede salter dannet med base, slik som et alkalimetallsalt, f.eks. natrium eller kalium, et jordalkalimetallsalt med f.eks. kalsium eller magnesium, et organisk aminsalt, f.eks. trietyl-amin, morfolin, N-metylpiperidin, N-etylpiperidin, prokain, dibenzylamin, N,N-dibenzyletylamnin eller aminosyrer, f.eks. lysin. Foretrukne farmasøytisk akseptable salter er natrium- og kaliumsalter.
Estere som er hydrolyserbare in vivo, er slike farma-søytisk akseptable estere som hydrolyserer i menneskekroppen og danner utgangsforbindelsen. Slike estere kan identifiseres ved å administrere forbindelsen som skal testes intravenøst til et testdyr, og deretter undersøke testdyrets kroppsvæsker. Egnede estere som er hydrolyserbare in vivo for karboksy, innbefatter Ci-6-alkoksymetylestere, som f. eks. metoksymetyl, d-6-alkanoyl- oksymetylestere, som f.eks. pivaloyloksymetyl, ftalidylestere og de ytterligere estere beskrevet i US 5 478 820.
Forbindelser anvendt i denne oppfinnelse er: N-t-butoksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyramid,
N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyramid,
N-t-butoksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-2-(4'-tetrahydropyranyl)acetamid,
N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-2-(4'-tetrahydropyranyl)acetamid,
N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3(S)-syklopropylbutyramid,
og farmasøytisk akseptable salter, enantiomerer, diastereomerer eller in vivo hydrolyserbare estere eller blandinger derav.
Ytterligere forbindelser ifølge denne oppfinnelse er beskrevet i tabell 1.
og farmasøytisk akseptable salter, enantiomerer, diastereomerer eller blandinger derav.
Ytterligere andre forbindelser ifølge denne oppfinnelse er vist i tabell 2.
og farmasøytisk akseptable salter, enantiomerer, diastereomerer eller blandinger derav.
Foretrukne forbindelser anvendt ifølge denne oppfinnelse er: N-t-butoksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyramid,
N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyramid,
N-t-butoksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-2-(4<1->tetrahydropyranyl)acetamid,
N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-2-(4'-tetrahydropyranyl)acetamid,
N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3(S)-syklopropylbutyramid,
og farmasøytisk akseptable salter, enantiomerer, diastereomerer eller in vivo hydrolyserbare estere eller blandinger derav.
For å anvende en forbindelse ifølge krav 1 eller et farmasøytisk akseptabel salt, en enantiomer, diastereomer eller blanding derav for terapeutisk behandling av pattedyr, innbefat-tende mennesker, spesielt for behandling av antraks eller inhibere letal faktor, blir den normalt formulert i henhold til standard farmasøytisk praksis som et farmasøytisk preparat.
Forbindelsene anvendt i den foreliggende oppfinnelse, kan administreres i en terapeutisk effektiv mengde intravenøst, subkutant, intramuskulært eller ved enhver annen metode som er kjent av fagfolk på området (f.eks. rektal, oral, parenteral). Et egnet farmasøytisk preparat anvendt ifølge denne oppfinnelse er et som er fremstilt for steril injeksjon, og som inneholder mellom 1 og 50 vekt% av forbindelsene anvendt ifølge denne oppfinnelse .
Egnede subjekter for administrasjon av formuleringen ifølge den foreliggende oppfinnelse innbefatter primater, mennesker og andre dyr, særlig mennesker og husdyr som katter, kaniner og hunder.
De følgende eksempler er gitt for å demonstrere den foreliggende oppfinnelse, og de viser at forbindelsene ifølge denne oppfinnelse er anvendelige for behandling av antraks og inhibering av letal faktor.
Definisjon av begreper:
Eksempel 1
N-t-butoxy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyramid (1,8 g, 4,99 mmol ble oppløst i 75 ml vannfritt dikloretan som inneholdt etanol (0,30 ml, 5 mmol) ved 0 °C. Hydrogenkloridgass ble boblet inn i 30 minutter. Kolben ble lukket med et septum, og reaksjonsblandingen ble omrørt i 2 døgn. Etter at løsningsmidlet var fjernet i en rotavap, ble residuet oppløst i metanol (1-2 ml) og fortynnet med DCM
(20 ml). De dannede krystaller ble samlet opp og vasket med mer DCM, hvilket ga etter vakuumtørking N-hydroxy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyramid.
NMR (500 MHz, CD3OD) 8: 0,86 (d, 3 H) , 0,91 (d, 3 H) , 1,86 (m, 1 H), 2,30 (d, 3 H), 3,30 (d, 1 H) , 7,16 (t, 1 H) , 7,67 (m, 1 H) , 7,72 (m, 1 H) .
Startmaterialet for eksempel 1 ble fremstilt som følger: D-valin (1,39 g, 11,9 mmol) ble oppløst i 80 ml dioksan/vann (1:1) som inneholdt K2CO3(3,3 g, 24 mmol). En opp-løsning av 4-fluor-3-metylfenylsulfonylklorid (10 mmol) i dioksan (4 ml) ble dryppet inn under god omrøring. Reaksjonsblandingen ble omrørt ved romtemperatur i 30 minutter. Etylacetat (80 ml) og 1 N HC1 (50 ml) ble tilsatt. Det organiske lag ble vasket med 1 N HC1 to ganger og ekstrahert med 5 % K2C03
(3 x 25 ml). De kombinerte basiske ekstrakter ble surgjort og
ekstrahert med etylacetat (80 ml). Det organiske lag ble vasket med saltvann (2 x) og tørket over Na2S04. Løsningsmidlet ble fjernet i rotavap, og residuet ble triturert med heksan. Det resulterende faste stoff ble tørket, hvilket ga 2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylsmørsyre.
2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylsmør-syre (2,64 g, 9,12 mmol) ble oppløst i DCM (30 ml), fulgt av tilsetning av DIEA (3,18 ml, 2 ekv.) og 0-t-butylhydroksylamin-hydroklorid (2,3 g, 2 ekv.). EDC.HC1 (2,1 g, 1,2 ekv.) ble deretter tilsatt porsjonsvis som et fast stoff. Mer EDC (0,6 g,
0,5 ekv.) ble tilsatt etter 40 minutter, og reaksjonsblandingen ble omrørt i ytterligere 30 minutter. Løsningsmidlet ble fjernet i en rotavap ved romtemperatur, og residuet ble fordelt mellom etylacetat (80 ml) og 1 N HC1 (50 ml). Det organiske lag ble vasket med 1 N HC1, saltvann og så tørket over Na2S04. Råproduk-tet ble flashkolonnerenset med etylacetat i DCM med en løsnings-middelgradient fra 5 % til 12 %, hvilket ga produktet N-t-butoksy-2 (R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyr-amid som et hvitt skum.
TLC (1:10 etylacetat:DCM) Rf 0,16, NMR (500 MHz, CD3OD) 8: 0,89 (d, 3 H), 0,90 (d, 3 H), 1,08 (s, 9H), 1,86 (m, 1 H) , 2,30 (d, 3 H), 3,44 (d, 1 H), 7,18 (t, 1 H), 7,70 (m, 1 H), 7,77 (m, 1 H) .
Eksempel 2
Eksempel 2, N-hydroksy-2(R)-[(4-fluor-3-metylfenyl-sulfonyl) ] amino-2- (4 ' -tetrahydropyranyl) acetamid, ble fremstilt av D-4<1->tetrahydropyranylglysin på samme måte som eksempel 1.
NMR (500 MHz, CD3OD) 8: 1,19 (m, 1 H) , 1,34 (m, 1 H) , 1,40 (m, 1 H), 1,74 (m, 1 H), 1,80 (m, 1 H), 2,32 (d, 3 H), 3,31 (m, 2 H), 3,37 (d, 1 H), 3,90 (m, 2 H, 7,18 (t, 1 H), 7,65 (m, 1 H) , 7,72 (m, 1 H) .
Eksempler 3- 143
Eksempler 3-143 i tabell 1, ble fremstilt i fast fase og kan illustreres som følger:
Trinn 1
Harpiksfunksjonalisering
En oppløsning av N-hydroksyftalimid (2,8 g,17 mmol),DIEA (3,0 ml, 17 mmol) i diklormetan (30 ml) og DMF (15 ml) ble tilsatt hurtig til 4,39 g 2-klortritylharpiks (1,1 mmol/g fylling) i en smeltetilpasset patron. Harpikssuspensjonen ble ristet gjentatte ganger og hensatt på benken over natten.Harpiksen ble vasket 5 x med DMF, og deretter behandlet med en 40 ml hydrazinløsning (0,5 M i THF) i 2 timer. En stor mengde hvitt, fast stoff ble dannet rundt harpiksen. Dette ble vasket med DMF-H20 (1:1) 2 x, DMF 4 x. Hydrazinbehandlingen ble gjentatt en gang til i ytterligere 3 timer. Harpiksen ble vasket med DMF-H2O (1:1) 2 x, DMF 4 x, DCM 5 x, tørket i vakuum over natten, og dette ga 4,53 g harpiks 1. Fyllingen var ca. 1,0 mmol/g vektøkning.
Trinn 2
Fylling av aminosyre
Det 0-forankrede hydroksylaminharpiks 1, 500 mg (ca. 1,0 mmol/g fylling), ble svellet med DCM i en smeltetilpasset
patron og fikk renne av. En oppløsning av Fmoc-D-alloisoleucin (530 mg, 1,5 mmol, 3 ekv.), DIC (0,120 ml, 0,75 mmol, 1,5 ekv.) i 3 ml DMF ble tilsatt. Patronen ble ristet kort og hensatt på benken i 1 time. En ytterligere dose DIC (0,04 ml, 0,25 mmol,
0,5 ekv.) ble tilsatt. Etter enda 1 time ble harpiksen vasket med DMF 4 x, DCM 4 x og vakuumtørket over natten, hvilket ga harpiks 2. Den omtrentlige fylling var 0,70 mmol/g vektøkning.
Trinn 3
Harpiks 2, 150 mg, ca. 0,7 mmol/g fylling, ble behandlet med 2 ml piperidin/DMF (25 %) i 2 timer. Harpiksen ble vasket med MDF 3 x og DCM 3 x. En oppløsning av DIEA (73 |al, 0,42 mmol, 4 ekv.) i THF-DCM (1:1, 0,5 ml) som inneholdt DMAP (ca. 2 mg) ble tilsatt til harpiksen, fulgt av en oppløsning av 3-klorfenylsulfonylklorid (66 mg, 3 ekv.) i THF-DCM (0,5 ml). Etter 3 timer ble harpiksen vasket med DMF 3 x, DCM 3 x og spaltet to ganger med 5 % TFA/DCM (0,5 ml) i 30 minutter. Den kombinerte, spaltede oppløsning ble dampet inn, og residuet ble oppløst i CH3CN:H20 og så renset med reversfase-HPLC, hvilket ga eksempel 25, N-hydroksy-2(R)-(3-klorfenylsulfonyl)amino-3(S)-metylvaleriansyreamid.
NMR (500 MHz, CD3OD) 5: 0,82 (d, d, 6 H), 1,04 (m, 1 H), 1,35 (m, 1 H), 1,64 (m, 1 H) , 3,52 (d, 1 H) , 7,50 (t, 1 H) , 7,60 (d, 1 H), 7,76 (d, 1 H, 7,84 (m, 1 H).
I tabell 1 er det listet opp strukturer for eksemplene 3-144. Slik det vil forstås av gjennomsnittsfagmannen, ble eksemplene 4-144 fremstilt i henhold til beskrivelsen gitt i eksempel 3, med noen modifikasjoner. Noen forbindelser krevde et avbeskyttelsestrinn (behandling med 50 % TFA/DCM) etter at harpiksen var spaltet av.
Eksempel 145
2(R)-[(4-fluor-3-metylfenyl)sulfonyl]amino-3(S)-syklo-propylsmørsyre (10 mg, 31 umol) ble oppløst i DMF (0,3 ml) med HOBt (4,5 mg, 0,031 mmol), DIEA (11 fil, 0, 062 mmol), O-trimetyl-silylhydroksylamin (20 |^1, 0,16 mmol). En oppløsning av PyBOP (20 mg, 0,038 mmol) i DMF (0,3 ml) ble tilsatt. Reaksjonen ble stanset etter 30 minutter med CH3CN:H20 (1:1, 5 % TFA), og reaksjonsblandingen ble passert gjennom reversfase-HPLC, som etter lyofilisering ga N-hydroksy-2(R)-[(4-fluor-3-metylfenyl)-sulfonyl]amino-3(S)-syklopropylbutyramid.
NMR (500 MHz, CD3OD) 8: -0,04 (m, 1 H), 0,20 (m, 1 H) , 0,35 (m, 1 H), 0,41 (m, 1 H), 0,54 (m, 1 H), 0,90 (d, 3 H) , 1,08 (m, 1 H), 2,32 (d, 3 H), 3,60 (d, 1 H), 7,17 (t, 1 H), 7,68 (m, 1 H), 7,75 (m, 1 H).
MS: 331,1 (M + H+) .
Startmaterialet for eksempel 145 ble fremstilt som følger:
Metylglykolat (10,4 g, 114 mmol) og krotylalkohol
(100 ml, overskudd) ble refluksert i nærvær av K2C03(0,8 g) i
1 time, og i løpet av denne tiden ble ca. 10 ml av kondensatet fjernet gjennom en Dean-Stark-felle. Etter fortynning med heksan (100 ml) ble fast stoff filtrert gjennom en kort silikagel-kolonne (50 g) og vasket med 1:5 etylacetat:heksan (250 ml). Det kombinerte filtrat og vaskevæskene ble konsentrert til 100 ml og så igjen fortynnet med heksan (100 ml), passert gjennom silika-gelkolonnen og vasket. Oppløsningen ble konsentrert til ca. 12,5 g olje, som ble vakuumdestillert og ga krotylglykolat:
9,3 g (97 °C/20 mmHg) som en blanding av cis:trans (1:10).
NMR (500 MHz, CDC13) 8: 1,3 (m, 3 H) , 4,15 (s, 2 H) , 4,62 (d, 2 H), 5,6 (m, 1 H), 5,84 (m, 1 H), cisisomer: 1,71 (m, 3 H), de resterende topper overlappet med transisomeren.
Det ovenfor fremstilte krotylglykolat (9,3 g, 71 mmol) i THF (10 ml) ble tilsatt sakte til en oppløsning av LiN(TMS)2
(200 ml, 1,0 M) i THF (200 ml) ved -78 °C. Etter 40 minutter ved denne temperatur ble trimetylsilylklorid (25,5 ml, 200 mmol) tilsatt. Kjølebadet ble fjernet, og reaksjonsblandingen ble omrørt over natten. Reaksjonsblandingen ble konsentrert til ca. 150 ml og fortynnet med etylacetat (500 ml). Dette ble vasket to ganger med 2 N HC1. Vaskevæskene ble ekstrahert med mer etylacetat. Det kombinerte organiske lag ble ekstrahert med 5 % K2CO33 x. Den kombinerte basiske oppløsning ble surgjort med kald konsentrert HC1 og ekstrahert med etylacetat. Etylacetat-løsningen ble vasket med mettet NaCl og tørket over Na2S04. Fordampning av løsningsmidlet og vakuumtørking ga 2-hydroksy-3-metylpropen-4-ensyre som en blanding av diastereomerer.
NMR (500 MHz, CD3OD) for diastereomer 1 [(2R,3S) og (2S,3R)] 5: 1,02 (d, 3 H), 2,60 (m, 1 H), 4,05 (d, 1 H), 5,02 (m, 1 H), 5,09 (m, 1 H), 5,87 (m, 1 H); diastereomer 2 [(2R,3R) og (2S,3S)] 8: 1,11 (d, 3 H), 2,6 (m, 1 H), 4,03 (d, 1 H), 5,0 (m,
1 H), 5,09 (m, 1 H), 5,80 (m, 1 H). Diastereomerforholdet ved NMR var ca. 7 til 1 med diastereomer 1 som hovedkomponent. Den ovenfor fremstilte syre (8,5 g, 65 mmol) ble opp-løst i tørt DMF (100 ml) og DIEA (16 ml, 91 mmol). Metyljodid (11,7 ml, 85 mmol) ble tilsatt. Dette ble omrørt i 15 timer og så fortynnet med etylacetat (500 ml) og vasket med 0,1 N HC1 3 x, saltvann 2 x og tørket over Na2S04. Fordampning av løsnings-midlet etterlot metyl-2-hydroksy-3-metylpenten-4-ensyreester. NMR (500 MHz, CD3OD) for diastereomer 1 [(2R,3S) og (2S,3R)] 8: 1,02 (d, 3 H) , 2,55 (m, 1 H) , 3,70 (s, 3 H) , 4,04 (d, 1 H), 5,02 (m, 1 H), 5,06 (m, 1 H), 5,81 (m, 1 H); diastereomer 2 [(2R,3R) og (2S,3S)] 8: 1,08 (d, 3 H), 2,58 (m, 1 H), 3,70 (s, 3 H), 4,07 (d, 1 H), 5,00 (m, 1 H), 5,06 (m, 1 H), 5,80 (m,
1 H) .
Den ovenfor fremstilte metylester (2,9 g, 20 mmol) ble oppløst i tørt DCM (100 ml) med dijodmetan (8,1 ml, 100 mmol) og avkjølt til 0 °C. En oppløsning av dietylsink (100 ml, 1,0 M i heksan) ble tilsatt. Kjølebadet ble fjernet, og blandingen ble omrørt under nitrogen i 3 døgn. En oppløsning av NH4C1 ble tilsatt for å stanse reaksjonen. Det organiske lag ble vasket med HC1 2 x, saltvann 2 x og tørket over Na2S04. Fordampning av løsningsmidlet etterlot en olje som inneholdt 70 % av produktet metyl-2-hydroksy-3-syklopropylbutyrat og 30 % av startmaterialet. Dette ble anvendt uten ytterligere rensing.
En oppløsning av den ovenfor fremstilte ester (3 g,
20 mmol), pyridin (2,0 ml, 24 mmol) i tørr DCM (10 ml) ble sakte tilsatt til en omrørt oppløsning av Tf20 (4,0 ml, 24 mmol) i DCM (100 ml) ved 0 °C. Etter 1 time ved 0 °C ble vann tilsatt for å stanse reaksjonen. Dette ble deretter vasket med fortynnet HC1 (0,1 N), saltvann og tørket over Na2S04. Fordampning av løsnings-midlet ga 5,3 g triflat som en olje. Dette ble omrørt med NaN3(2,4 g, 36 mmol) i DMF (80 ml) i 15 timer. Reaksjonsblandingen ble fortynnet med etylacetat (400 ml), vasket med fortynnet HC1 3 x, saltvann 2 x og tørket over Na2S04. Fordampning av løsnings-midlet etterlot 2,96 g olje. Flashkolonnekromatografi gjennom silikagel og eluering med 5 % eter i heksan ga metyl-2-azido-3-syklopropylbutyrat som en fargeløs olje. Den ønskede diastereomer 1 [(2R,3S) og (2S,3R)] kan isoleres gjennom preparativ reversfase-HPLC ved eluering med CH3CN:H20 som løsningsmiddel-gradient.
NMR (500 MHz, CDC13) for diastereomer 1 [(2R,3S) og (2S,3R)] 8: 0,04 (m, 1 H), 0,18 (m, 1 H), 0,48 (m, 2 H), 0,74 (m, 1 H), 1,09 (d, 3 H), 1,35 (m, 1 H), 3,80 (s, 3 H), 3,92 (d,
1 H) .
Den ovenfor isolerte aziddiastereomer [(2R,3S) og (2S,3R)] (400 mg, 2,2 mmol) ble oppløst i MeOH (10 ml) og av-kjølt i et vannbad ved 20 °C. Stannoklorid (860 mg, 4,4 mmol) ble tilsatt. Dette ble omrørt i 15 timer. Til reaksjonsblandingen ble det tilsatt dioksan (10 ml), K2C03(1,5 g, 10,1 mmol)/H20
(10 ml). Det faste stoff ble filtrert fra og vasket med dioksan (5 ml). Til det kombinerte filtrat og vaskevæskene ble det tilsatt en oppløsning av 4-fluor-3-metylfenylsulfonylklorid
(560 mg, 2,4 mmol) i dioksan (5 ml). Cirka 30 minutter senere ble reaksjonen surgjort med HC1 til pH 3 og fortynnet med CH3CN:H20. Produktet ble isolert gjennom preparativ reversfase-HPLC (gjentatte innsprøytninger) til metyl-2-(4-fluor-3-metyl-fenylsulfonamido)-3-syklopropylbutyrat. Ytterligere separasjon gjennom Chiralpk-kolonne AD og eluering med 7 % EtOH i heptan ga to enantiomerer, med den ønskede isomer 1 (2R,3S) eluert først.
NMR (500 MHz, CD3OD) 8: 0,01 (m, 2 H), 0,39 (m, 2 H), 0,62 (m, 1 H) , 1,01 (d, 3 H), 1,19 (m, 1 H), 2,312 (d, 3 H), 3,23 (s, 3 H), 3,90 (d, 1 H), 7,18 (t, 1 H), 7,68 (m, 1 H), 7,73 (m, 1 H) .
Metyl-2(R)-[(4-fluor-3-metylfenyl)sulfonyl]amino-3(S)-syklopropylsmørsyreester (20 mg, 0,061 mmol) ble oppløst i MeOH (0,2 ml), fulgt av tilsetning av LiOH (8 mg, overskudd)/H20 (0,15 ml). Etter at 2 timer ble reaksjonsblandingen surgjort med 1,5 ml CH3CN:H20 (1:1, 5 % TFA) og kromatografert med reversfase-HPLC, som ga 2(R)-(4-fluor-3-metylfenylsulfonamido)-3(S)-syklo-propylsmørsyre.
NMR (500 MHz, CD3OD) 8: -0,01 (m, 1 H) , 0,15 (m, 1 H) , 0,40 (m, 2 H), 0,65 (m, 1 H), 1,02 (d, 3 H), 1,22 (m, 1 H), 2,31 (d, 3 H), 4,83 (d, 1 H), 7,16 (t, 1 H), 7,69 (m, 1 H), 7,75 (m,
1 H) .
Eksempel 14 6
2(R)-[(4-fluor-3-metylfenyl)sulfonyl]amino-3(R)-syklo-pentoksylsmørsyre (11 mg, 0,03 mmol) ble oppløst i DMF (200fil) med DIEA (12 (il, 0,12 mmol), HOBt (8 mg, 0,06 mmol) og TMSONH2(10 ul, 0,08 mmol). En oppløsning av PyBOP (31 mg, 0,06 mmol) i DMF (100 ul) ble tilsatt. Reaksjonen ble stanset etter 20 minutter med 5 % TFA/H20, og produktet ble isolert med reversfase-HPLC, som etter lyofilisering ga N-hydroksy-2(R)-[(4-fluor-3-metylfenyl)sulfonyl]amino-3(R)-syklopentoksylbutyramid. NMR (500 MHz, CD3OD) 8: 0,97 (d, 3 H) , 1,44-1, 68 (m, 8 H), 2,32 (d, Jh-f, 3 H) , 3,61 (d, 1 H) , 3,72 (m, 1 H) , 3,67 (m, 1 H), 7,18 (m, 1 H), 7,70 (m, 1 H), 7,76 (m, 1 H). Startmaterialet, f.eks. 146, ble fremstilt som følger: N-trityl-D-treoninbenzylester (2,5 g, 5,5 mmol), TEA (2,8 ml, 20 mmol) ble oppløst i 100 ml tørt toluen ved -50 °C. En oppløsning av sulfurylklorid (800fal, 8 mmol) i toluen (20 ml)
ble tilsatt i løpet av 15 minutter. Reaksjonsblandingen fikk oppvarmes til romtemperatur. Etylacetat (100 ml) ble tilsatt, og dette ble vasket med mettet NaCl og tørket over Na2S04. Produktet ble krystallisert i MeOH (10 ml), hvilket ga benzyl-N-trityl-3(S)-metylaziridin-2(R)-karboksylat.
NMR (500 MHz, CDC13) 8: 1,37 (d, 3 H) , 1,64 (m, 1 H) , 1,95 (d, 1 H), 5,15 (d, J = 12 Hz, 1 H), 5,28 (d, J = 12 Hz, 1 H) , 7,19-7,28 (m, 12 H), 7, 33-7, 36 (m, 1 H), 7, 36-7, 39 (m, 3 H) , 7, 51-7, 54 (m, 4 H) .
Benzyl-N-trityl-3(S)-metylaziridin-2(R)-karboksylat (2,13 g, 4,92 mmol) ble oppløst i 20 ml MeOH:DCM (1:1) ved 0 °C, fulgt av tilsetning av TFA (20 ml). Etter omrøring ved romtemperatur i 1 time ble overskudd av reagens og løsningsmiddel fjernet i en rotavap (T < 25 °C) . Residuet ble fordelt mellom DCM (50 ml) og H20 (100 ml). Vannfasen ble vasket én gang med DCM, og pH ble justert til basisk med NaHC03og så ekstrahert med etylacetat og tørket over Na2S04. Fjerning av løsningsmidlet etterlot 650 mg benzyl-3(S)-metylaziridin-2(R)-karboksylat. Dette ble oppløst i DMF (15 ml) ved 0 °C. TEA (2,1 ml, 15 mmol) ble tilsatt, fulgt av BOC20 (1,64 g, 7,5 mmol). Reaksjonsblandingen ble omrørt ved romtemperatur over natten. Etylacetat (100 ml) og H20 (100 ml) ble tilsatt, det organiske lag ble vasket med 10 % sitronsyre to ganger, med saltvann og så tørket over Na2S04. Rå-produktet ble flashkolonnekromatografert ved eluering med løsningsmiddelgradient med 5 %-10 % etylacetat/heksan som inneholdt 0,1 % TEA, hvilket ga benzyl-N-Boc-3(S)-metylaziridin-2(R)-karboksylat.
NMR (500 MHz, CD30D) 8: 1,21 (d, 3 H), 1,44 (s, 9H), 2,82 (m, 1 H), 3,21 (d, 1 H), 5,2 (q, 2 H), 7,30-7,38 (m, 5 H).
Benzyl-N-Boc-3(S)-metylaziridin-2(R)-karboksylat
(50 mg, 0,17 mmol) og syklopentylalkohol (0,5 ml, 5,5 mmol) ble oppløst i DCM (0,5 ml), fulgt av noen få dråper BF3.Et20. Dette ble omrørt ved romtemperatur i 10 timer. Løsningsmidlet ble fjernet, og residuet ble renset gjennom reversfase-HPLC. Produktet ble samlet opp og behandlet med 50 % TFA/DCM, som ga benzyl-2(R)-amino-3(R)-syklopentoksylbutyrattrifluoracetat.
NMR (500 MHz, CD3OD) 8: 1,28 (d, 3 H), 1,4-1,7 (m, 8 H) , 3,92 (m, 1 H), 4,06 (d, 1 H) , 4,14 (dq, 1 H) , 5,26 (d, J = 12 Hz, 1 H), 5,31 (d, J =12 Hz, 1 H), 7,38 (m, 3 H), 7,43 (m, 2 H).
Benzyl-2(R)-amino-3(R)-syklopentoksylbutyrattrifluor-acetat (63 mg, 0,16 mmol), DIEA (174 ul, 1,0 mol) og DMAP (1 mg) ble oppløst i dioksan (2 ml), fulgt av sakte tilsetning av en oppløsning av 4-fluor-3-metylfenylsulfonylklorid (ca. 0,33 mmol) i dioksan (1 ml). Etter 15 minutter ble reaksjonen stanset med 5 % TFA/H2O og renset med reversfase-HPLC, hvilket ga benzyl-2(R)-[(4-fluor-3-metylfenyl)sulfonyl]amino-3(R)-syklopentoksyl-butyrat. Den beskyttende gruppe for benzylesteren ble fjernet ved hydrogenering i MeOH:EA (1 ml) med 10 % Pd/C (2 mg) over natten, hvilket ga 2(R)-[(4-fluor-3-metylfenyl)sulfonyl]amino-3(R)-syklopentoksylsmørsyre.
Med noen modifikasjoner som er kjent av fagfolk på området, ble eksempler 147-153 i tabell 2 utført i henhold til eksempel 146.
Analyse for bestemmelse av inhibering av letal faktor
Analysen nedenfor er beskrevet av Cummings et al., PNAS, 14. mai 2002, vol. 99, nr. 10, s. 6603-6606, og PCT-søknad US03/05552 (US patentsøknad nr. 60/359707). Analysen ble benyttet til å bestemme inhibering av letal faktor etter omsetning med en forbindelse som antas å være en inhibitor for letal faktor.
Inhibitorforbindelser for letal faktor kan anvendes til videre undersøkelser av den letale faktorens aktivitet og de inhiberende forbindelser med passende farmakologiske egenskaper som kan anvendes til hjelp for å behandle eller forhindre antraks. Passende farmakologiske egenskaper innbefatter virk-ningsfullhet, metabolisme og fravær av uakseptable bivirkninger.
Effektiv screening av inhibitorer for letal faktor kan anvendes til å kartlegge for å identifisere dem som påvirker aktiviteten til letal faktor. Effektiv screening gjøres lettere ved en analyse som lett kan automatiseres og hvor det anvendes lave nivåer av renset enzym.
Måling av aktivitet
Letalfaktorsubstrater kan anvendes ved fremgangsmåter for målig av aktivitet av Bacillus anthracis letalfaktor og virkningen av en forbindelse på slik aktivitet. Slike metoder innebærer å inkubere et letalfaktorsubstrat beskrevet her med Bacillus anthracis letalfaktor ved å anvende et inkuberings-medium hvor Bacillus anthracis letalfaktor er aktiv, og det kan innbefatte nærvær av en forbindelse som skal testes. Spalting av substratet kan detekteres som et mål på aktivitet av Bacillus anthracis letalfaktor, eller virkningen av en forbindelse på aktivitet av letal faktor. Målinger kan være kvalitative eller kvantitative. For forbindelsene ifølge oppfinnelsen er resultatet av bindingsanalyse IC5oav letalfaktorenzym i området fra 15 uM eller lavere. Spesielt er IC50for N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyramid og N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-2-(4'-tetra-hydropyranyl) acetamid på henholdsvis 0,13 uM og 0,06 uM.
Claims (7)
1. Forbindelse,
karakterisert vedat den er valgt blant: N-t-butoksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyramid, N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyramid, N-t-butoksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-2-(4'-tetrahydropyranyl)acetamid, N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-2-(4'-tetrahydropyranyl)acetamid, N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3(S)-syklopropylbutyramid;
og fra tabellene 1 og 2 nedenfor:
og farmasøytisk akseptable salter, enantiomerer, diastereomerer eller blandinger derav.
Ytterligere andre forbindelser ifølge denne oppfinnelse er vist i tabell 2.
og farmasøytisk akseptable salter, enantiomerer, diastereomerer eller blandinger derav.
2. Forbindelse ifølge krav 1, hvor den er valgt blant: N-t-butoksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyramid, N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyramid, N-t-butoksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-2-(4'-tetrahydropyranyl)acetamid, N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-2-(4'-tetrahydropyranyl)acetamid, N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3(S)-syklopropylbutyramid,
og farmasøytisk akseptable salter, enantiomerer, diastereomerer eller blandinger derav.
3. Forbindelse ifølge krav 2, hvor den er: N-hydroxy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-3-metylbutyramid eller N-hydroksy-2(R)-[(4-fluor-3-metylfenylsulfonyl)]amino-2-(4'-tetrahydropyranyl)acetamid, eller
farmasøytisk akseptable salter, enantiomerer, diastereomerer eller blandinger derav.
4. Farmasøytisk preparat,
karakterisert vedat det omfatter en forbindelse ifølge krav 1-3, og en farmasøytisk akseptabel bærer.
5. Anvendelse av en forbindelse ifølge hvilket som helst av krav 1-3, for tilvirkning av et medikament for å inhibere aktiviteten av letal faktor (LF) frigjort fra bakterier i et patterdyr.
6. Anvendelse ifølge krav 5, hvor medikamentet i tillegg omfatter ett eller flere kjente legemidler valgt blant beta-laktamer, aminoglykosider, inhibitorer av beta—laktamase, renale tubulære blokkeringsmidler og inhibitorer av metaboli-serende enzymer, og N-acylerte aminosyrer.
7. Anvendelse ifølge krav 6, hvor de kjente legemidler er valgt blant imipenem, meropenem, vankomycin, cilastatin, cefoksitin, penicillin, klavulansyre, probenecid, tetrasyklin, ciprofloxacin og norfloxacin eller en blanding derav, og når imipenem anvendes som et legemiddel, anvendes det i kombinasjon med cilastatin.
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AU (1) | AU2003239599B8 (no) |
BR (1) | BR0311136A (no) |
CA (1) | CA2487727C (no) |
CY (1) | CY1109245T1 (no) |
DE (1) | DE60327432D1 (no) |
DK (1) | DK1511472T3 (no) |
EC (1) | ECSP045452A (no) |
ES (1) | ES2323527T3 (no) |
HR (1) | HRP20041138A2 (no) |
IL (2) | IL165259A0 (no) |
IS (1) | IS7517A (no) |
MA (1) | MA27257A1 (no) |
MX (1) | MXPA04011767A (no) |
NO (1) | NO329290B1 (no) |
NZ (1) | NZ536189A (no) |
PL (1) | PL374117A1 (no) |
PT (1) | PT1511472E (no) |
RU (1) | RU2289575C2 (no) |
SI (1) | SI1511472T1 (no) |
UA (1) | UA76059C2 (no) |
WO (1) | WO2003101382A2 (no) |
ZA (1) | ZA200408650B (no) |
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