NO314302B1 - Matriksmetalloproteinase-inhibitorer, anvendelse derav samt farmasöytisk blanding - Google Patents
Matriksmetalloproteinase-inhibitorer, anvendelse derav samt farmasöytisk blanding Download PDFInfo
- Publication number
- NO314302B1 NO314302B1 NO19994125A NO994125A NO314302B1 NO 314302 B1 NO314302 B1 NO 314302B1 NO 19994125 A NO19994125 A NO 19994125A NO 994125 A NO994125 A NO 994125A NO 314302 B1 NO314302 B1 NO 314302B1
- Authority
- NO
- Norway
- Prior art keywords
- methoxy
- piperidine
- benzenesulfonyl
- carboxylic acid
- alkyl
- Prior art date
Links
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- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 title description 3
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 19
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- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- -1 4-(4-n-butoxy- benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidin-4-carboxylic Chemical compound 0.000 claims description 15
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- 230000002401 inhibitory effect Effects 0.000 claims description 10
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- WWVKBGIBCFSFOJ-UHFFFAOYSA-N 4-(4-butoxyphenyl)sulfonyl-n-hydroxy-1-(3-phenoxypropyl)piperidine-4-carboxamide Chemical compound C1=CC(OCCCC)=CC=C1S(=O)(=O)C1(C(=O)NO)CCN(CCCOC=2C=CC=CC=2)CC1 WWVKBGIBCFSFOJ-UHFFFAOYSA-N 0.000 claims description 4
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- KHHADIVHVMPMRM-UHFFFAOYSA-N ethyl 4-(4-butoxyphenyl)sulfonyl-1-(2-phenoxyethyl)piperidine-4-carboxylate Chemical compound C1=CC(OCCCC)=CC=C1S(=O)(=O)C1(C(=O)OCC)CCN(CCOC=2C=CC=CC=2)CC1 KHHADIVHVMPMRM-UHFFFAOYSA-N 0.000 description 1
- FWHUHOBZYWQXCG-UHFFFAOYSA-N ethyl 4-(4-butoxyphenyl)sulfonyl-1-(2-phenylethoxy)piperidine-4-carboxylate Chemical compound C1=CC(OCCCC)=CC=C1S(=O)(=O)C1(C(=O)OCC)CCN(OCCC=2C=CC=CC=2)CC1 FWHUHOBZYWQXCG-UHFFFAOYSA-N 0.000 description 1
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- HSTSPDIMHZEZDT-UHFFFAOYSA-N ethyl 4-(4-butoxyphenyl)sulfonyl-1-[(4-methoxyphenyl)methyl]piperidine-4-carboxylate Chemical compound C1=CC(OCCCC)=CC=C1S(=O)(=O)C1(C(=O)OCC)CCN(CC=2C=CC(OC)=CC=2)CC1 HSTSPDIMHZEZDT-UHFFFAOYSA-N 0.000 description 1
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- MFMDAOMSCGOFGX-UHFFFAOYSA-N ethyl 4-(4-methoxyphenyl)sulfonyl-1-[(4-phenylphenyl)methyl]piperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC)(S(=O)(=O)C=2C=CC(OC)=CC=2)CCN1CC(C=C1)=CC=C1C1=CC=CC=C1 MFMDAOMSCGOFGX-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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- C07C323/51—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
- 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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Description
Foreliggende oppfinnelse vedrører matriksmetaHoproteinase-inhibitorer, anvendelse derav samt farmasøytisk blanding.
Matriksmetalloproteinaser (MMP'er) er en gruppe av enzymer som er blitt tillagt den patologiske ødeleggelse av bindevev og basalmembraner. Disse sinkholdige endopeptidaser består av flere undergrupper av enzymer innbefattet kollagenaser, stromelysiner og gelatinaser. Av disse klasser, er gelatinasene blitt vist å være de MMP'er som sterkest knyttet til veksten og spredningen av tumorer. Det er kjent at ekspresjonsnivået av gelatinase er forhøyet i malignanser, og at gelatinase kan bryte ned basalmembranen, hvilket fører til tumormetastase. Angiogenese, som er nødvendig for veksten av faste tumorer, er også nylig blitt vist å ha en gelatinasekomponent i sin patologi. Videre er det tegn som tyder på at gelatinase er involvert i sprenging av plakk i forbindelse med aterosklerose. Andre tilstander som befordres av MMP'er, er restenose, MMP-betinget osteopeni, inflammatoriske sykdommer i sentralnervesystemet, aldring av hud, tumorvekst, osteoartritt, reumatoid artritt, septisk artritt, sårdannelse i hornhinnen, unormal sårheling, bensykdom, proteinuri, aneurysmal aortasykdom, degenerativt brusktap som følge av traumatisk leddskade, demyelinerende sykdommer i nervesystemet, skrumplever, glomerulær sykdom i nyrene, for tidlig sprenging av fostermembran-er, inflammatorisk tarmsykdom, periodontal sykdom, aldersrelatert makulær degenerasjon, diabetisk retinopati, proliferativ vitreoretinopati, retinopati ved for tidlig fødsel, øyebetennelse, keratokonus, Sjøgren's syndrom, nærsynthet, øye-tumorer, okulær angiogenese/ neovaskularisering og avstøtning av hornhinne-implantat. For nyere oversikter se: (1) Recent Advances in Matrix Metallo-proteinase Inhibitor Research, R.P. Beckett, A.H. Davidson, A.H. Drummond, P. Huxley og M. Whittaker, Research Focus, vol. 1,16-26,
(1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16, (3) Curr. Medicinal Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther. Patents (1995) 5(2): 1087-110, (5) Exp. Opin. Ther.
Patents (1995) 5(12): 1287-1196.
TNF-a-omdannende enzym (TACE) vil katalysere dannelsen av TNF-ct fra membranbundet TNF-a-forløperprotein. TNF-a er et pro-inflammatorisk cytokin som nå blir antatt å spille en rolle ved reumatoid artritt, septisk sjokk, avstøtning av implantat, kakeksi, anoreksi, betennelse, kongestiv hjertesvikt, inflammatorisk sykdom i sentralnervesystemet, inflammatorisk tarmsykdom, insulinresistens og HIV-infeksjon i tillegg til sine vel dokumenterte antitumoregenskaper. For eksempel har forskning med anti-TNF-a-anti-stoffer og transgene dyr demonstrert at blokkering av dannelsen av TNF-a vil inhibere progresjonen av artritt. Denne observasjon er nylig blitt utvidet også til mennesker.
Det er ventet at småmolekylinhibitorer av MMP'er og TACE derfor vil ha potensiale for behandling av flere forskjellige sykdomstilstander. Selv om flere forskjellige MMP og TACE-inhibitorer er blitt identifisert og beskrevet i litteraturen, er den overveiende majoritet av disse molekyler peptidiske og peptidlignende forbindelser som skulle forventes å ha biotilgjengelighet og farmakokinetiske problemer vanlige for slike forbindelser som ville begrense deres kliniske effektivitet. Lavmolekylære, potente, langtidsvirkende, oralt biotilgjengelige inhibitorer av MMP'er og/eller TACE er derfor være svært ønskelige for den potensielle kroniske behandling av de ovenfor nevnte sykdomstilstander.
Nylig er det fremkommet to referanser (U.S. 5.455.258 og europeisk patent-søknad 606.046) som beskriver arylsulfonamido-substituerte hydroksyaminsyrer. Disse dokumenter dekker forbindelser som for eksempel CGS 27023A. Disse er de eneste ikke-peptidmatirksmetalloproteinase-inhibitorer beskrevet inntil i dag.
Salah et al., Liebigs Ann. Chem. 195, (1973) beskriver noen arylsubstituerte tio og arylsubstituerte sulfonylacetohydroksaminsyrederivater med den generelle formel L Disse forbindelser ble fremstilt for å studere Mannich-reaksjonen. Deretter ble de testet for sin fungicidaktivitet.
Noen sulfonkarboksylsyrer er beskrevet i US patent 4.933.367. Disse forbindelser ble vist å ha hypoglykemisk aktivitet.
Den foreliggende oppfinnelse vedrører nye, lavmolekylære, ikke-peptid-inhibitorer av matriksmetalloproteinaser (MMP'er) og TNF-a-omdannende enzym (TACE) som kan anvendes for behandling av artritt, tumormetastase, sårdannelse i vev, unormal sårheling, periodontal sykdom, bensykdom, diabetes (insulinresistens) og HIV-infeksjon.
Ifølge denne oppfinnelse tilveiebringes forbindelsen, kjennetegnet ved formel 1
hvori R<1> er fenyl, eventuelt substituert med Q-Ce-alkoksy;
A er -S-, -SO- eller S02-;
R og R , sammen med det karbonatom som de er bundet til, danner en piperidinring som eventuelt er N-substituert med en gruppe valgt fra: fenyl-Ct-Gj-alkyl (som igjen kan være substituert med C|-C6-alkoksy, halogen, Ci-C6-alkyl eller piperidyl-C|-C6-alkoksy), naftyl, bifenyl-Ci-C6-alkyl, C2-Cio-alkenyl, Ci-Cg-alkyl, C4-Cio-cykIoalkyl eller fenoksy-Ci-Ce-alkyl;
R<4> er hydrogen;
eller et farmasøytisk akseptabelt salt derav.
De mest foretrukne matriksmetalloproteinase- og TACE-inhiberende forbindelser ifølge denne oppfinnelse er: 4-(4-metoksy-benzensulfonyl)-l-(3-fenylpropyl)-piperidin-4-karboksylsyre-hydroksyamid, l-tert-butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-cyklooktyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-etyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-isopropyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-metyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-benzyI-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-(4-fluor-benzyl)-4-(4-metoksy-benzensulfonyl)-pipeirdin-4-karboksylsyrehydroksyamid, l-(4-fluor-benzyl)-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, 4-(4-metoksy-benzensulfonyl)-l-(4-metoksybenzyl)-piperidin-4-karboksylsyrehydroksy-amid, 4-(4-metoksy-benzensulfonyl)-1-[2-(4-^ hydroksyamid,
4-(4-metoksy-benzensulfonyl)-l-(2-fenyl-etyl)-piperidin-4-karboksylsyre-hydroksyamid, 4-(4-n-butoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksylsyre-hydroksyamid,
4-(4-metoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksylsyre-hydro amid,
4-(4-n-butoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksylsyre-hydroksyamid,
4-(4-metoksy-benzensulfonyl)-l-(2-fenoksy-etyl)-piperidin-4-karboksylsyre-hydroksyamid,
4-(4-n-butoksy-benzensulfonyl)-l-(2-fenyl-etyl)-pipeirdin-4-karboksylsyrehydroksyamid og
4-(4-metoksy-benzensulfonyl)-1 -[4-(2-piperidin-1 -yl-etoksy)-benzyl]-piperidin-4-karboksylsyre-hydroksyamid.
Det skal forstås at definisjonen av forbindelsene med formel 1 når R<1>, R<2>, R<3> og R<4 >inneholder asymmetriske karbonatomer, skal omfatte alle mulige stereoisomerer og blandinger derav som har den nedenfor diskuterte aktivitet. Spesielt skal den omfatte racemiske modifikasjoner og eventuelle optiske isomerer som har den angitte aktivitet. Optiske isomerer kan fremstilles i ren form ved standard separasjonsteknikk. Hvor ikke angitt på annen måte, skal betegnelsen "alkyl" referere til en rettkjedet eller forgrenet Ct-Cealkylgruppe. De farmasøytisk akseptable salter er de som er avledet fra farmasøytisk akseptable organiske og uorganiske syrer så som melke-syre, sitronsyre, eddiksyre, vinsyre, ravsyre, maleinsyre, eplesyre, saltsyre, hydrogenbromidsyre, fosforsyre, salpetersyre, svovelsyre, metansulfonsyre og lignende kjente akseptable syrer.
Den foreliggende oppfinnelse tilveiebringer følgelig en farmasøytisk blanding, kjennetegnet ved at den omfatter en farmasøytisk bærer og en terapeutisk effektiv mengde av en matriksmetalloproteinase eller TACE-inhiberende forbindelse ifølge formelen
hvori R<1> er fenyl, eventuelt substituert med én eller to grupper
uavhengig valgt fra R<5>;
cykloalkyl med 3 til 8 karbonatomer, eventuelt substituert med Ci-Cealkoksy; A er -S-, -SO- eller S02-;
R<2> og R<3>, sammen med det karbonatom som de er bundet til, danner en piperidinring som eventuelt er N-substituert med en gruppe valgt fra: fenyl-Ci-C4-alkyl (som kan være substituert med Ci-Ce-alkoksy, halogen, Ci-C6-alkyl eller piperidyl-Ci-C6-alkoksy), naftyl, bifenyl-Ci-Cg-alkyl, C2-Cio-alkenyl, Ci-Cg-alkyl,
C4-Cio-cykloalkyl eller fenoksy-Cj-Ce-alkyl;
R<4> er hydrogen;
eller et farmasøytisk akseptabelt salt derav.
Foreliggende oppfinnelse vedrører videre anvendelse av en terapeutisk effektiv mengde av en matriksmetalloproteinase-inhiberende forbindelse med formelen
hvori R1 er fenyl, eventuelt substituert med Ci-C6-alkoksy; A er -S-, -SO- eller S02-; R<2> og R<3>, sammen med det karbonatom som de er bundet til, danner en piperidinring som eventuelt er N-substituert med en gruppe valgt fra: fenyl-Ci-C4-alkyl (som igjen kan være substituert med CrC6-alkoksy, halogen, Ct-Cg-alkyl eller piperidyl-Ci-Ce-alkoksy), naftyl, bifenyl-Ci-C6-alkyl, C2-Cio-alkenyl, Cj-Cs-alkyl, C4-Cio-cykloalkyl eller fenoksy-Ci-Ce-alkyl; R<4> er hydrogen; eller et farmasøytisk akseptabelt salt derav for fremstilling av et farmasøytisk preparat for inhibering av patologiske forandringer formidlet av matriksmetalloproteinaser i pattedyr. Det er videre beskrevet anvendelse av en terapeutisk effektiv mengde av en TACE-inhiberende forbindelse med formelen
hvori R<1> er fenyl, eventuelt substituert med én eller to grupper
uavhengig valgt fira R<5>;
cykloalkyl med 3 til 8 karbonatomer, eventuelt substituert med Ci-C6alkoksy;
A er -S-, -SO- eller S02-;
R<2> og R<3>, sammen med det karbonatom som de er bundet til, danner en piperidinring som eventuelt er N-substituert med en gruppe valgt fra: fenyl-Ci-d-alkyl (som kan være substituert med Ci-C6-alkoksy, halogen, Ci-C6-alkyl eller piperidyl-Ci-Cfi-alkoksy), naftyl, bifenyl-Ci-Ce-alkyl, C2-Cio-alkenyl, Ci-Cg-alkyl,
Cij-Cio-cykloalkyl eller fenoksy-Ci-C6-alkyl;
R<4> er hydrogen;
eller et farmasøytisk akseptabelt salt derav for fremstilling av et farmasøytisk preparat for inhibering av patologiske forandringer formidlet av TNF-ct-omdannende enzym (TACE) i pattedyr.
Blandingene er fortrinnsvis tilpasset for oral administrering. De kan imidlertid være tilpasset for andre administreringsmåter, for eksempel parenteral administrering for pasienter.
For å oppnå konsistens i administreringen, blir det foretrukket at en blanding ifølge denne oppfinnelse er i form av en enhetsdose. Egnede enhets-doseformer inkluderer
tabletter, kapsler og pulvere i småposer eller ampuller. Slike enhetsdoseformer kan inneholde fra 0,1 til 100 mg av en forbindelse ifølge denne oppfinnelse. Forbindelsene ifølge den foreliggende oppfinnelse kan administreres oralt i et doseområde fra ca. 0,01 til 100 mg pr. kg. En slik blanding kan administreres fra 1 til 6 ganger om dagen, mer vanlig
. fra 1 til 4 ganger om dagen.
Blandingene ifølge denne oppfinnelse kan formuleres med konvensjonelle eksipienter, slik som fyllstoffer, et disintegreringsmiddel, et bindemiddel, et smøre-middel, et smaksmiddel og lignende. De formuleres på konvensjonell måte.
Forbindelsene ifølge den foreliggende oppfinnelse kan fremstilles ifølge én av de generelle fremgangsmåter vist nedenfor.
Det hensiktsmessig substituerte merkaptanderivat ble alkylert ved anvendelse av enten substituert (skjema 1) eller usubstituert (skjema 2) a-bromeddiksyre-esterderivat i tilbakeløpende aceton ved anvendelse av K2CO3 som base. Det således oppnådde sulfid-derivat ble oksidert ved anvendelse av m-klorperbenzo-syre i CH2CI2 eller ved anvendelse av okson i metanol/vann. Sulfonet oppnådd fra ovennevnte fremgangsmåte, kan enten ytterligere alkyleres ved anvendelse av flere forskjellige alkylhalogenider for å oppnå det disubstituerte derivat eller det kan hydrolyseres ved anvendelse av NaOH:MeOH ved romtemperatur. Istedenfor å anvende etylesteren, dersom den tertiære butylester er tilstede, kan hydrolysen imidlertid utføres med TFA:CH2Cl2 ved romtemperatur. Deretter ble den oppnådde karboksylsyre omdannet til hydroksaminsyrederivatet ved omsetning med oksalylklorid/DMX (katalytisk) og hydroksylamin/trietylamin.
a. K^CCVaceton/tilbakeløp; b. m-klorperbenzosyre; c. K2CO3/18-krone-6/R3Br/aceton/tilbakeløp; d. NaOH/MeOH/THF/RT;
e. (COCl)2/CH2Cl2/Et3N/NH2OH»HCl.
a. K2C03/aceton/tilbakeløp; b. m-klorperbenzosyre; c. K2CO3/18-krone-6/R2Br/aceton/tilbakeløp; d. R3Br/10 NNaOH/BzN(Et)3/CH2Cl2/RT;
e. NaOH/MeOH/THF/RT;
f. (COCl2/CH2Cl2/Et3N/NH20H.HCl
Som vist i skjema 3, kan sulfidderivatet videre alkyleres ved anvendelse av litium-bis(trimetylsilyl)amid i THF ved 0°C. Den alkylerte eller mono-substituerte forbindelse ble hydrolysert og omdannet til hydroksaminsyrederivatet. Sulfinyl-derivatene ble fremstilt ved oksydasjon av sulfidhydroksaminsyrederivatene med H2O2 i MeOH-løsning.
a. K2C03/aceton/tilbakeløp; b. R3Br/HMDS/THF; c. NaOHMeOH/THF/RT; d. (COCl)2/CH2Cl2/Et3N/NH2OH.HCl;
e. MeOH/H202/RT.
De tilsvarende 1 -substituerte-4-(4-metoksy-benzensulfonyl)pipeirdin-4-karboksyl-syrehydroksyamider ble fremstilt ved å starte fra dietanolamin og hensiktsmessig substituerte alkyl eller arylhalogenider (skjema 4). De N-substituerte dietanolaminderivater ble omdannet til diklorforbindelsene ved anvendelse av tionylklorid. De tilsvarende diklorider ble omsatt med substituerte sulfonyleddiksyreetylesterderivater i nærvær av K2C03/18-krone-6 i kokende aceton. l-Substituerte-4-(4-etoksybenzen-sulfonyl)-piperidin-4-karboksylsyre-etylestere oppnådd på denne måte, ble omdannet til hydroksyamidet som vist i skjema 4. Alternativt kan disse klasser av Forbindelser og andre heterocykler fremstilles som angitt i skjema 5 og 6.
Alternativt skal skjema 7 til 11 vise fremgangsmåter for fremstilling av hydroks-aminsyreforbindelser ved anvendelse av en fasrfasebærer (P).
Reagenser og betingelser:
a) 2-Halogensyre (3,0 ekv.); 1-hydroksybenzotriazol-hydrat (HOBt, 6,0 ekv.); 1,3-di-isopropylkarbodiimid (D1C, 4,0 ekv.); DMF, 25°C; 2-16 timer. b) Tiol (5,0 ekv.); natriumjodid (5,0 ekv.); l,8-diazabicyklo[5.4.0]undek-7-en (DBU, 3,0 ekv.); THF; 25°C; 12-16 timer. c) 70% tert-butylhydroperoksyd (40 ekv.); benzensulfonsyre (2,0 ekv.); DCM; 25°C; 12-24 timer.
d) mCPBA (5,0 ekv.); DCM; 25°C; 12-24 timer.
e) TFA:DCM (1:1); 25°C; 1 time.
4-0-MetylhydroksyIaminfenoksymetylkopoly(styren-l%-divinylbenzen)-harpiksen
(hydroksylaminharpiksen) kan kobles med en 2-halogensyre under dannelse av hydroks-amatesterharpiksen. Koblingsreaksjonen kan utføres i nærvær av karbodiimid, slik som D1C, i et inert løsningsmiddel slik som DMF, ved romtemperatur. Halogengruppen kan erstattes med en tiol i nærvær av en base, slik som DBU, i et inert løsningsmiddel slik som THF, ved romtemperatur. Sulfidet kan oksideres til sulfoksidet ved omsetning med et oksydasjonsmiddel så som tert-butylhydroperoksyd, i nærvær av en syrekatalysator så som benzensulfonsyre, i et inert løsningsmiddel så som DCM, ved romtemperatur. Alternativt kan sulfidet oksyderes til sulfonet ved omsetning med et oksydasjonsmiddel slik som meta-
klorperoksybenzosyre, i et inert løsningsmiddel så som DCM, ved romtemperatur. Sulfidet, sulfoksidet eller sulfonet kan behandles med en syre, så som trifiuor-eddiksyre, i et inert løsningsmiddel så som DCM, for å frigjøre den frie hydroks-aminsyre.
Skjema 8 viser en fremgangsmåte for fremstilling av hydroksaminsyrer som har alkoksygrupper bundet til den aromatiske ring.
Reagenser og betingelser:
a) 2-Halogensyre (3,0 ekv.); 1-hydroksybenzotriazol-hydrat (HOBt, 6,0 ekv.); 1,3-diisopropylkarbodiimid (D1C, 4,0 ekv.); DMF, 25°C; 2-16 timer. b) 4-Fluorbenzentiol (5,0 ekv.); natriumjodid (5,0 ekv.); l,8-diazabicyklo-[5.4.0]-undek-7-en (DBU, 3,0 ekv.); THF; 25°C; 12-16 timer.
c) Alkohol (15,0 ekv.); natriumhydrid (15,0 ekv.); DMF; 80°C; 15 timer.
d) 70% tert-butylhydroperoksyd (40 ekv.); benzensulfonsyre (2,0 ekv.); DCM; 25°C; 12-24 timer.
e) mCPBA (5,0 ekv.); DCM; 25°C; 12-24 timer.
f) TFA:DCM (1:1); 25°C; 1 time.
Hydroksylaminharpiksen kan kobles med 2-halogensyren, og halogen-gruppen kan erstattes med fluorbenzentiol som tidligere beskrevet. Fluorgruppen kan deretter erstattes med en alkohol i nærvær av en base så som natriumhydrid, i et inert løsningsmiddel så som DMF, ved ca. 80°C. Alkoksybenzensulfanyl-hydroksamatesteren kan deretter oksideres enten til den tilsvarende sulfmyl eller sulfonylhydroksamatester som tidligere beskrevet. De frie hydroksaminsyrer kan frigjøres som tidligere beskrevet.
Skjema 9 viser en fremgangsmåte for fremstilling av 2-bisarylsulfanyl-, sulfinyl- og sulfonylhydroksaminsyrer.
Reagenser og betingelser:
a) 2-Halogensyre (3,0 ekv.); 1-hydroksybenzotriazol-hydrat (HOBt, 6,0 ekv.); 1,3-diisopropylkarbodiimid (D1C, 4,0 ekv.); DMF, 25°C; 2-16 timer. b) 4-Brombenzentiol (5,0 ekv.); natriumjodid (5,0 ekv.); l,8-diazabi-cyklo[5.4.0]-undek-7-en (DBU, 3,0 ekv.); THF; 25°C; 12-16 timer. c) 70% tert-butyl-hydroperoksyd (40 ekv.); benzensulfonsyre (2,0 ekv.); DCM; 25°C; 12-24 timer.
d) mCPBA (5,0 ekv.); DCM; 25°C; 12-24 timer.
e) Arylboronsyre (2,0 ekv.); tetrakis-(trifenylfosfin)palladium(0) (0,1 ekv.); 10% vandig natriumkarbonat (10,0 ekv.); DME; 80°C; 8 timer.
f) TFA:DCM (1:1); 25°C; 1 time.
Hydroksylaminharpiksen kan kobles med 2-halogensyren, og halogen-gruppen kan erstattes med brombenzentiol som tidligere beskrevet. Brombenzen-sulfanylhydroksamat-esteren kan deretter oksyderes enten til den tilsvarende sulfinyl eller sulfonylhydroksamatester som tidligere beskrevet. Bromgruppen kan deretter erstattes med en arylgruppe ved omsetning med arylboronsyre i nærvær av en katalysator så som tetrakis(trifenylfosfin)-palladium(O), og en base slik som natriumkarbonat, i et inert løsningsmiddel slik som DME, ved ca. 80°C. De frie hydroksaminsyrer kan frigjøres som tidligere beskrevet.
Skjema 10 viser en fremgangsmåte for fremstilling av hydroksaminsyrer som har amingrupper bundet til den aromatiske ring.
Reagenser og betingelser:
a) 2-Halogensyre (3,0 ekv.); 1-hydroksybenzotriazol-hydrat (HOBt, 6,0 ekv.); 1,3-diisopropylkarbodiimid (D1C, 4,0 ekv.); DMF, 25°C; 2-16 timer. b) 4-Brombenzentiol (5,0 ekv.); natriumjodid (5,0 ekv.); l,8-diazabicyklo-[5.4.0]-undek-7-en (DBU, 3,0 ekv.); THF; 25°C; 12-16 timer. c) Amin (20,0 ekv.); tris(dibenzylidenaceton)dipalladium(0) (0,2 ekv.); (S)-(-)-2,2'-bis(difenylfosfino)-l,l'-binaftyl ((S)-BINAP, 0,8 ekv.); natrium-tert-butoksyd (18,0
ekv.); dioksan; 80°C; 8 timer.
d) TFA:DCM (1:1); 25°C, 1 time.
Hydroksylaminharpiksen kan kobles med 2-halogensyren, og halogen-gruppen kan erstattes med brombenzentiol som tidligere beskrevet. Bromgruppen kan deretter erstattes med et amin i nærvær av en katalysator så som tris(di-benzylidenaceton)dipalladium(0), og en ligand så som (S)-BINAP, og en base så som natrium-tert-butoksyd, i et inert løsnings-middel slik som dioksan, ved ca. 80°C. De frie hydroksaminsyrer kan frigjøres som tidligere beskrevet.
Skjema 11 viser en fremgangsmåte for fremstilling av hydroksaminsyrer som har sulfonatgrupper bundet til den aromatiske ring.
Reagenser og betingelser:
a) 2-Halogensyre (3,0 ekv.); 1-hydroksybenzotriazol-hydrat (HOBt, 6,0 ekv.); 1,3-diisopropylkarbodiimid (D1C, 4,0 ekv.); 25°C; 2-16 timer. b) 4-Hydroksybenzentiol (5,0 ekv.); natriumjodid (5,0 ekv.); l,8-diazabi-cyklo[5.4.0]-undek-7-en DBU, 3,0 ekv.); THF; 25°C; 12-16 timer.
c) Sulfonylklorid (5,0 ekv.); trietylamin (2,0 ekv.); DCM; 25°C; 8 timer.
d) 70% tert-butylhydroper-oksid (40 ekv.); benzensulfonsyre (2,0 ekv.); DCM; 25°C; 12-24 timer.
e) mCPBA (5,0 ekv.); DCM; 25°C; 12-25 timer.
f) TFA:DCM (1:1); 25°C; 1 time.
Hydroksylaminharpiksen kan kobles med 2-halogensyren, og halogen-gruppen kan erstattes med hydroksybenzentiol som tidligere beskrevet. Hydroksybenzensulfanyl-hydroksamatesteren kan deretter oksyderes enten til den tilsvarende sulfinyl eller sulfonylhydroksamatester som tidligere beskrevet. Hydroksygruppen kan deretter sulfonyleres ved omsetning med et sulfonylklorid i nærvær av en base så som trietytamin, i et inert løsningsmiddel slik som DCM, ved ca. romtemperatur. De frie hydroksaminsyrer kan frigjøres som tidligere beskrevet.
De følgende eksempler er presentert for å illustrere rammen for denne oppfinnelse. HPLC-renhet av forbindelser fremstilt ved kombinatoriske fremgangsmåter, er presentert som arealprosentsats ved en foreskrevet bølgelengde (% @ nm).
Eksempel 1
l-Benzyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid
Til en omrørt løsning av 4-metoksy-benzentiol (2,8 g, 20 mmol) og vannfritt K2CO3 (10 g, overskudd) i tørr aceton (100 ml), ble tilsatt a-brom-etylacetat (3,3 g, 20 mmol) i en rundbunnet kolbe, og reaksjonsblandingen ble oppvarmet med tilbakeløp i 8 timer med god omrøring. Til slutt fikk reaksjonsblandingen avkjøle seg, og kaliumsaltene ble frafiltrert, og reaksjonsblandingen ble konsentrert. Residuet ble ekstrahert med kloroform og vasket med H2O og 0,5 N NaOH-løsning. Det organiske sjikt ble ytterligere vasket godt med vann, tørket over MgSC"4, filtrert og konsentrert. (4-Metoksy-fenyl-sulfanyl)-eddiksyre-etylester ble isolert som en blekgul olje. Utbytte 4,4 g (100%); MS: 227 (M+H)<+>.
Til en omrørt løsning av 60% 3-kIorperoksybenzosyre (14,0 g, 40 mmol) i metylenklorid (100 ml) ved 0°C; ble langsomt tilsatt (4-metoksy-fenylsulfanyl)-eddiksyre-etylester (4,4 g, 20 mmol) i CH2C12 (15 ml). Reaksjonsblandingen ble raskt tåket og ble omrørt ved romtemperatur i 6 timer. Reaksjonsblandingen ble deretter fortynnet med heksaner (300 ml) og omrørt i 15 minutter. De faste stoffer ble frafiltrert, og Na2SC>3-løsning ble tilsatt til det organiske sjikt som ble omrørt i minst 3 timer før blandingen ble ekstrahert med CHC13 og vasket med H2O. Det organiske sjikt ble tørket over MgSC«4, filtrert og konsentrert, og den fargeløse (4-metoksy-fenylsulfonyl)-eddiksyre-etylester ble isolert som en olje. Utbytte 100%; MS: 259 (M+H)<+.>
Til en omrørt løsning av dietanolamin (10,5 g, 100 mmol) og vannfritt K2CC>3 (30 g, overskudd) i tørr aceton (250 ml), ble tilsatt benzylbromid (17,2 g, 100 mmol) i en rundbunnet kolbe, og reaksjonsblandingen ble oppvarmet med tilbake-løp i 8 timer under god omrøring. Til slutt fikk reaksjonsblandingen avkjøle seg, og kaliumsaltene ble frafiltrert, og reaksjonsblandingen ble konsentrert. Residuet ble ekstrahert med kloroform og vasket med H2O. Det organiske sjikt ble ytterligere vasket godt med vann, tørket over MgS04, filtrert og konsentrert. Fargeløs olje. Utbytte 19,0 g, 97%; MS: 196 (M+H).
N-Benzyldietanolamin (9,75 g, 50 mmol) ble løst i mettet metanolisk saltsyre og konsentrert til tørrhet. Det således dannede hydroklorid ble løst i metylenklorid (300 ml), og tionylklorid (20 g, overskudd) ble tilsatt dråpevis og omrørt ved romtemperatur i 1 time. Til slutt ble reaksjonsblandingen konsentrert til tørrhet, og produktet bis-(2-klor-etyl)-benzylaminhydroklorid ble anvendt for ytterligere om-danning uten noen rensing. Utbytte 13,0 g, 97%; smp.; MS: 232 (M+H).
Til en omrørt løsning av bis-(2-klor-etyl)-benzyIamin-hydroklorid (6,6 g, 24,7 mmol), 18-krone-6 (500 mg) og vannfritt K2CO3 (30 g, overskudd) i tørr aceton (250 ml), ble tilsatt (4-metoksy-fenylsulfonyl)-eddiksyre-etylester (6,12 g, 24 mmol) i en rundbunnet kolbe, og reaksjonsblandingen ble oppvarmet med tilbakeløp i 16 timer under god omrøring. Til slutt fikk reaksjonsblandingen avkjøle seg, og kaliumsaltene ble frafiltrert, og reaksjonsblandingen ble konsentrert. Residuet ble ekstrahert med kloroform og vasket med H2O. Det organiske sjikt ble ytterligere vasket godt med vann, tørket over MgSCU, filtrert og konsentrert. Den mørke brune reaksjonsblanding ble renset ved silikagel-kolonnekromatografi ved eluering med 30% etylacetat:heksan, og produktet 4-(4-metoksy-benzensulfonyl)-l-benzyl-pipeirdin-4-karboksylsyre-etylester ble isolert som en brun olje. Utbytte 6,0 g, 60%; MS: 418 (M+H).
4-(4-Metoksy-benzensulfonyl)-l -benzyl-piperidin-4-karboksylsyre-etylester (5,0 g, 11,9 mmol) ble løst i MeOH:THF (1:1, 200 ml) og omrørt ved romtempera-tur i 72 timer. Til slutt ble reaksjonsblandingen konsentrert, og produktet nøytralisert med konsentrert HC1 ved å løse det i vann (200 ml). Etter nøytraliseringsreaksjonen, ble blandingen konsentrert til tørrhet. Iskaldt vann (100 ml) ble tilsatt til det faste stoff og filtrert. Produktet 4-(4-metolcsy-benzensulfonyl)-l-benzyl-piperidin-4-karboksylsyre, ble tørket ved 50°C og tatt til det neste trinn uten noen rensing. Fargeløst fast stoff. Utbytte 3,2 g, 69%; MS: 390 (M+H).
Til en omrørt løsning av 4-(4-metoksy-benzensulfonyl)-l-benzyl-piperidin-4-karboksylsyre (2,0 g, 5,1 mmol) og DMF (2 dråper) i CH2C12 (100 ml) ved 0°C, ble tilsatt oksalylklorid (1,0 g, 8 mmol) på dråpevis måte. Etter tilsetningen, ble reaksjonsblandingen omrørt ved romtemperatur i 1 time. Samtidig, i en separat kolbe, ble en blanding av hydroksylamin-hydroklorid (2,0 g, 29 mmol) og trietyl-amin (5 ml, overskudd) omrørt i THF:vann (5:1,30 ml) ved 0°C i 1 time. Ved slutten av 1 time, ble oksalylklorid-reaksjonsblandingen konsentrert, og det blek-gule residuum ble løst i 10 ml CH2CI2 og langsomt tilsatt til hydroksylaminet ved 0°C. Reaksjonsblandingen ble omrørt ved romtemperatur i 24 timer og konsentrert. Det oppnådde residuum ble ekstrahert med kloroform og vasket godt med vann. Det oppnådde produkt ble renset ved silikagel-kolonnekromatografi og eluert med kloroform, og produktet 4-(4-metoksybenzen-sulfonyl)-l-benzyl-piperidin-4-karboksylsyre-hydroksyamid ble isolert som et fargeløst fast stoff. Smp. 90-95°C; utbytte 1,2 g, 48%; MS: 405 (M+H)<+>;
<l>H NMR (300 MHz, DMSO-d6): 5 2,29 (m, 3H), 2,76-2,79 (m, 2H), 3,43 (m, 4H), 4,30 (s, 2H), 7,14-7,17 (d, 2H), 7,50-7,73 (m, 5H), 9,37 (s, 1H), 10,53 (s, 1H), 11,18 (s, 1H).
Eksempel 2
4-(4-Metoksy-benzensulfonyl)-l-(3-metoksy-benzyl)-piperidin-4-karboksylsyre-hydroksyamid
2- [(2-Hydroksy-etyl)-(3-metoksy-benzyl)-amino]-etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanol-amin (3,1 g, 29,5 mmol) og 3-metoksybenzylklorid (5 g, 31,9 mmol). Utbytte 9,28 g (99%); gul olje; MS: 226 (M+H).
3- Metoksybenzyl-bis-(2-klor-etyl)-amin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel l, ved å starte fra 3-metoksy-benzyl-dietanolamin (4,4 g, 20 mmol). Utbytte 4,5 g (93%); gult fast stoff; smp. 86-88°C; MS: 263 (M+H)<+>.
4- (4-Metoksy-benzensulfonyl)-l-(3-metoksy-benzyl)-piperidin-4-karboksylsyre-etylesterble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (5,0 g, 22 mmol) og bis-(2-klor-etyl)-(3-metoksy-benzyl)-amin (8,0 g, 23,5 mmol). Utbytte 2,4 g (24%); lavtsmeltende fast stoff; MS: 447,9 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-1 -(3-metoksy-benzyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-(3-metoksy-benzyl)-piperidin-4-karboksylsyre-etylester (2,4 g, 5,36 mmol) løst i metanol (30 ml), 10N natriumhydroksyd (10 ml), tetrahydrofuran (20 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 710 mg (32%); hvitt fast stoff; smp. 199°C; MS: 419,9 (M+H)<+.>
Ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-(3-metoksy-benzyl)-piperidin-4-karboksylsyre (10 mg, 1,98 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 190 mg av 4-(4-metoksy-benzensulfonyl)-l-(3-metoksy-benzyl)-piperidin-4-karboksylsyre-hydroksyamid som et hvitt fast stoff. Smp. 130°C; utbytte 20,4%; MS: 435,0 (M+H)<+>;
'H NMR (300 MHz, DMSO-de): 5 2,24-2,32 (m, 2H), 2,51 (d, 2H), 2,73-2,1 (m, 2H), 3,37 (d, 2H), 3,76 (s, 3H), 3,88 (s, 3H), 4,32 (s, 2H), 7,01-7,77 (m, 8H), 9,38 (s, 1H), 10,1 (s, 1H).
Eksempel 3
l-(3,4-Diklort)enzyl)-4-(4-metoksy-benzemulfonyl)-piperidin-4-karboksylsyre-hydroksyamid
2-[(2-Hydroksy-etyl)-(3,4-diklor-benzyl)-amino]-etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanolamin (4,84 g, 46 mmol) og 3,4-diklorbenzylklorid (9,0 g, 46 mmol). Utbytte 13,8 g (99%); fargeløs olje; MS: 264,3 (M+H)<+>.
3,4-Diklorbenzyl-bis-(2-klor-etyl)-amin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 3,4-diklorbenzyl-dietanol-amin (10,7 g, 41 mmol). Utbytte 99%; gult fast stoff; smp. 218-220°C; MS: 301,8 (M+H)<+>. l-(3,4-Diklorbenzyl)-4-(metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (2,9 g, 11 mmol) og 3,4-diklorbenzyl-bis-(2-kloretyl)-amin (3,4 g, 11 mmol). Utbytte 5,9 g (60%); brun olje; MS: 494,5 (M+H)<+>. l-(3,4-Diklorbenzyl)-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksyl-syreble fremstilt ved å starte fra l-(3,4-diklorbenzyl)-4-(metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester (5,0 g, 10 mmol) løst i metanol (50 ml), 10 N natriumhydroksyd (15 ml) og teti^ydrofuran (75 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 2,94 (62%); MS: 458,3 (M+H)<+>.
Ved å starte fra l-(3,4-diklorbenzyl)-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre (2,67 g, 5,8 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isoelrt 0,2 g av l-(3,4-dikloTbenzyl)-4-(4-metoksy-benzen-sulfonyl)-piperidin-4-karboksylsyre-hydroksyamid som et hvitt fast stoff. Smp. 192-195°C; utbytte 10%; MS: 472,9 (M+H)";
'H NMR (300 MHz, DMSO-dfi): 5 2,20-2,28 (m, 2H), 2,76-2,79 (m, 2H), 3,43-3,44 (m, 4H), 4,30 (s, 2H), 7,14-7,17 (d, J=0,030,2H), 7,50-7,73 (d, J=0,027, 1H), 7,65-7,68 (d, J=0,029,2H), 7,72-7,75 (d, J=0,027,2H), 7,87 (s, 1H), 9,37 (s, 1H), 10,53 (s, 1H), 11,18 (s, 1H).
Eksempel 4
4-(4-Metoksy-benzensulfonyl)-l-(4-metylbenzyl)-piperidin-4-karboksyIsyre-hydroksyamid
2-[(2-Hydroksy-etyl)-(4-metyl-benzyl)amino]-etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanolamin (4,8 g, 46 mmol) og 4-metylbenzyl-klorid (8,5 g, 46 mmol). Utbytte 9,8 g (99%); MS: 209,9
(M+H)<+>.
4-Metylbenzyl-bis-(2-klor-etyl)-amin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-metyl-benzyl-dietanolamin (6 g, 20 mmol). Utbytte 5,2 g (84%); gult fast stoff; smp. 145-147°C; MS: 245,9 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-l-(4-metylbenzyl)-piperidin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (7,0 g, 27 mmol) og 4-metyl-bis-(2-kloretyl)-amin (5,0 g, 17 mmol). Utbytte 4,64 g (63%); lavt-smeltende fast stoff; MS: 431,9 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-1 -(4-metylbenzyI)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra 4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksyl-syre-etylester (4,3 g, 9,9 mmol) løst i metanol (30 ml), 10 N natriumhydroksyd (10 ml), tetrahydrofuran (20 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 1,6 g (40%); hvitt fast stoff; smp. 207-208°C; MS: 404,3 (M+H)<+>.
Ved å starte fra4-(4-metoksy-benzensulfonyl)-l-(4-metylbenzyl)-piperidin-4-karboksylsyre (1,59 g, 3,9 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 0,505 g av 4-(4-metoksy-benzensulfonyl)-l-(4-metylbenzyl)-piperidin-4-karboksylsyre-hydroksyamid som et hvitt fast stoff. Smp. 176-I77°C; utbytte 32%;
MS: 419,0 (M+H)<+>;
'H NMR (300 MHz, DMSO-d6): 5 2,24-2,32 (m, 2H), 2,51 (t, 3H), 2,73-2,80 (m, 2H), 3,35-3,50 (m, 4H), 3,87 (s, 3H), 4,24 (s, 2H), 7,13-7,17 (d, J=0,039, 2H), 7,23-7,60 (d, J=0,036,2H), 7,38-7,41 (d, J=0,025, 2H), 7,65-7,68 (d, J=0,039,2H).
Eksempel 5
4-(4-Metoksy-benzensulfonyl)-l-naftalen-2-yl-metylpiperidm^ hydroksyamid
2-[(2-Hydroksy-etyl)-(2-naftyl-2-ylmetyl)amino]etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanolamin (6,18 g, 59 mmol) og 2-brommetyl)naftalen (10 g, 45 mmol). Utbytte 12,7 g (96%); gult fast stoff; smp. 162-164°C; MS: 246,0 (M+H)<+>.
2-Naftyl-2-ylmetyl-bis-(2-kloretyl)aniin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 2-naftyl-ylmetyl-dietanol-amin (10 g, 36 mmol). Utbytte 9,1 g (79%); brunt fast stoff; smp. 124-126°C; MS: 281,9 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-naftaIen-ylmetylpipeirdin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (8,4 g, 32 mmol) og 1-naftalen-ylmetyl-bis-(2-kloretyl)amin (8,6 g, 27 mmol). Utbytte 6,5 g (52%); lavtsmeltende fast stoff; MS: 440,0 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-l-naftalen-ylmetylpiperidin-4-l«irboksylsyreble fremstilt ved å starte fra 4-(4-metoksy-benzensulfonyI)-naftalen-ylmetyl-piperidin-4-karboksylsyre-etylester (6,3 g, 13 mmol) løst i metanol (30 ml), 10N natriumhydroksyd (30 ml) og tetrahydrofuran (30 ml). Den resulterende reaksjons-blanding ble opparbeidet som vist i eksempel 1. Utbytte 2,3 g (36%); gult fast stoff; smp. 226-228°C; MS: 440,0
(M+H)\
Ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-naftalen-2-yl-metyl-piperidin-4-karboksylsyre (2,18 g, 5,0 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 0,753 g av 4-(4-metoksy-benzensulfonyl)-l-naftalen-2-yl-metylpiperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt fast stoff. Smp. 168-170°C; utbytte 31%; MS: 455,0 (M+H)<+>;
'H NMR (300 MHz, DMSO-de): 8 2,29-2,33 (m, 2H), 2,86-2,89 (m, 2H), 3,42-3,46 (m, 4H), 3,85 (s, 3H), 4,46 (s, 2H), 7,13-7,16 (d, J=0,030,2H), 7,56-7,64 (m, 3H), 7,65-7,68 (d, J=0,030,2H), 7,98-8,00 (m, 3H), 8,21 (s, 1H), 10,70 (s, 1H), 11,20 (s, 1H).
Eksempel 6
l-Bifenyl-4-ylmetyl-4-(4-metoksy-te hydroksyamid
2-[(2-Hydroksy-etyl)-(l-bifenyl-4-ylmetyl))-amino]etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanol-amin (5,2 g, 49 mmol) og 4-(klormetyl)bifenyl (10 g, 49 mmol). Utbytte 9,98 g (66%); hvitt fast stoff; smp. 160-162°C; MS: 271,9 (M+H)<+>. Denne ble omdannet til dikloridet som vist i eksempel 1. l-Bifenyl-4-ylmetyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyreetylester (2,85 g, 11 mmol) og l-bifenyl-4-ylmetyl-bis-(2-klor-etyl)amin (3,4 g, 11 mmol). Utbytte 2,1 g(39%); beige fast stoff; smp. 176-178°C; MS: 494,1 (M+H)<+>.
1- Bifenyl-4-ylmetyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra l-bifenyl-4-ylmetyl-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester (5,7 g, 12 mmol) løst i etanol (20 ml), tetra-hydrofuran (20 ml) og 10 N natriumhydroksyd (10 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 2,1 g (39%); MS: 465,8 (M+H)<+>.
Ved å starte fra l-bifenyl-4-ylmetyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre (1,0 g, 2,2 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 0,132 g av I-bifenyl-4-ylmetyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid som et gullenbrunt fast stoff. Smp. 168°C; utbytte 20%; MS: 440,9 (M+H)<+>;
<]>H NMR (300 MHz, DMSO-d*): 5 2,30-2,35 (m, 2H), 2,1-2,87 (m, 2H), 3,35-3,5 (m, 4H), 3,87 (s, 3H), 7,15-7,721 (d, J=0,059 Hz, 2H), 7,49-7,65 (m, 5H), 7,68-7,74 (d, J=0,06 Hz, 2H), 9,3 (s, 1H), 10,3 (s, 1H), 11,15 (s, 1H).
Eksempel 7
4-(4-Metoksy-benzensulfonyl)-l-(3-metyl-but-2-enyl)-piperidin-4-karboksylsyre-hydroksyamid
2- [(2-Hydroksy-etyl)-l-(3-metyl-but-2-enyl)-amino]etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanol-amin (4,1 g, 39
mmol) og 4-brom-2-metyI-buten (6,0 g, 40 mmol). Utbytte 98%; brun olje; MS: 173,8
(M+H)<+>.
1- (3-Metyl-but-2-enyl)-bis-(2-klor-etyl)amin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 2-[(2-hydroksy-etyl)-l-(3-metyl-but-2-enyl)amino]etanol (10, 4 g, 50 mmol). Utbytte 10,5 g (99%); brunt fast stoff; MS: 210,3
(M+H).
4-(4-Metoksy-benzensulfonyl)-l-(3-metyl-but-2-enyl)-piperidin-4-karboksyl-syre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensuIfonyl)-eddiksyre-etylester (11,32 g, 44 mmol) og 3-metyl-but-2-enyl-bis-(2-kloretyl)amin (10,4 g, 50 mmol). Utbytte 6,2 g (36%); brun olje; MS: 395,6 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-l-(3-metyl-but-2-enyl)-piperidin-4-karboksyl-syre ble fremstilt ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-(3-metyl-but-2-enyl)-piperidin-4-karboksylsyre-etylester (6,2 g, 16 mmol) løst i etanol (15 ml), 10 N natriumhydroksyd (10 ml) og tetrahydrofuran (75 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 1,2 g (21%); brun fast stoff; smp. 196-197°C; MS: 367,9 (M+H)<+>.
Ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-(3-metyl-but-2-enyl)-piperidin-4-karboksylsyre (1,0 g, 3,0 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 110 mg av 4-(4-metoksy-benzensulfonyl)-l-(3-metyl-but-2-enyl)-piperidin-4-karboksylsyre-hydroksyamid som et gult fast stoff. Smp. 142-145°C; utbytte 12%; MS: 382,9 (M+H)<+>;
<!>H NMR (300 MHz, DMSO-de): 8 1,67 (s, 3H), 1,79 (s, 3H), 2,18-2,23 (m, 2H), 2,66-2,73 (m, 2H), 3,37-3,46 (rn, 2H), 3,67-3,69 (m, 2H), 5,19-5,24 (m, 1H), 7,15-7,18 (d, J=0,03, 2H), 7,67-7,70 (d, J=0,030,2H), 9,34 (s, 1H), 9,88 (s, 1H), 11,15 (s, 1H).
Eksempel 8
l-(4-Brom-benzyl)-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid
2- [(4-Brombenzyl)-(2-hydroksy-etyl)amino]etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanolamin (22,5 g, 150 mmol) og 4-brombenzylbromid (25 g, 100 mmol). Utbytte 33,66 g (99%); gul olje; MS: 273,8
(M+H)<+>.
(4-Brom-benzyl)-bis-(2-kloretyl)amin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å stare fra 2-[(4-brombenzyI)-(2-hydroksy-etyl)amino]etanol (33,28 g, 122 mmol). Utbytte 47 g (99%); brunt fast stoff; smp. 125°C; MS: 309,8 (M+H)<+>. l-(4-Brom-benzyl)-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (8,6 g, 33,5 mmol) og 4-brombenzyl)-bis-(2-kloretyl)amin (13,3 g, 38,6 mmol). Utbytte 17 g (44%); brun olje; MS: 497,8 (M+H)<+>.
1- (4-Brom-benzyl)-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra l-(4-brom-benzyl)-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester (16,5 g, 33,3 mmol) løst i THF:metanol 3:1 og 10 N NaOH (20 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 6,18 g (40%); gyllenbrunt fast stoff; smp. 215°C; MS: 469,7 (M+H)<+>.
Ved å starte fra l-(4-brom-benzyl)-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre (1,95 g, 4,2 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 1,29 g av l-(4-brom-benzyI)-4-(4-metoksy-benzen-sulfonyI)-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt fast stoff. Utbytte 60%; smp. 180°C; MS: 484,7 (M+H)<+>;
'H NMR (300 MHz, DMSO-d6): 8 2,18-2,29 (m, 2H), 2,46 (d, 2H), 2,74-7,89 (m, 2H), 3,39 (d, 2H), 3,87 (s, 3H), 4,28 (s, 2H), 7,18 (d, J=17 Hz, 2H), 7,49 (d, J=8,l Hz, 2H), 7,65-7,68 (m, 4H), 9,37 (s, 1H), 10,5 (s, 1H).
Eksempel 9
4-(4-Metoksy-benzensulfonyl)-l-(3-fenyl-propyl)-piperidin-4-karboksylsyre-hydroksyamid
2- [(2-Hydroksy-etyl)-(3-fenyl-propyl)amino]etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanolamin (15,8 g, 151 mmol) og l-brom-3-fenylpropan (20 g, 101 mmol). Utbytte 21,31 g (95%); gul olje; MS: 223,9 (M+H)<+>.
Bis-2-(klor-etyl)-(3-fenyl-propyl)-amin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 2-[(2-hydroksy-etyl)-(3-fenyl-propyl)-amino]etanol (20,32 g, 90,7 mmol). Utbytte 24,9 g (92%); brun olje; MS: 259,8
(M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-l-(3-fenyl-propyl)-piperidin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)eddiksyre-etylester (12 g, 46,5 mmol) og bis-(2-klor-etyI)-(3-fenyl-propyl)amin (24,8 g, 93,8 mmol). Utbytte 11,24 g (54%); brun olje; MS: 446 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-1 -(3-fenyl-propyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-(3-fenyl-propyl)-piperidin-4-karboksylsyre-etylester (10,74 g, 24,13 mmol) løst i THF:metanol 3:1 og 10 N NaOH (40 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 4,67 g (47%); nesten hvitt pulver; smp. 203°C; MS: 418,2 (M+H)<+>.
Ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-(3-fenyl-propyl)-piperidin-4-karboksylsyre (4,37 g, 10,4 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 1,64 g av 4-(4-metoksy-benzensulfonyI)-l-(3-fenyl-propyl)-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt fast stoff. Utbytte 37%; smp. 143°C; MS: 432,9 (M+H)<+>;
<!>H NMR (300 MHz, DMSO-de): 6 1,92-1,97 (m, 2H), 2,18-2,29 (m, 2H), 2,47 (d, 2H), 2,58 (t, J=7,7 Hz, 2H), 2,6-2,73 (m, 2H), 3,0-3,06 (m, 2H), 3,60 (d, J=12,3 Hz, 2H), 3,87 (s, 2H), 7,15-7,30 (m, 3H), 7,68 (d, J=9 Hz, 2H), 9,3 (s, 1H), 10,1 (s, 1H).
Eksempel 10
l-tert-Butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid
tert-Butyl-bis-(2-kloretyl)amin ble fremstilt ifølge den generelle fremgangs-måte som vist i eksempel 1, ved å starte fra 1-tert-butyl-dietanolamin (6 g, 37,2 mmol). Utbytte 11,15 g (99%); hvitt fast stoff; MS: 197,8 (M+H)<+.>
l-tert-ButyI-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (10 g, 38,76 mmol) og tert-butyl-bis-(2-kloretyl)amin (5,25 g, 22,53 mmol). Utbytte 5,37 g (62%); brun olje; MS: 348 (M+H)<+. >1 -tert-Butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra l-tert-butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester (5,37 g, 14 mmol) løst i metanol (300 ml) og 10 N NaOH (23 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 1,52 g (30,6%); hvitt pulver; smp. 204°C; MS: 356 (M+H)<+>.
Ved å starte fra l-tert-butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre (320 mg, 0,9 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 190 mg av l-tert-butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid som et grønt fast stoff. Utbytte 52%; smp. 40°C; MS: 371,1
(M+H)<+>;
<!>H NMR (300 MHz, DMSO-d6): 6 1,29 (s, 9H), 1,54 (m, 2H), 1,66 (m, 2H), 2,39 (m, 2H), 2,98 (m, 2H), 3,88 (s, 3H), 7,18 (d, 2H), 7,67 (d, 2H).
Eksempel 11
l-Butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid
Butyl-bis-(2-kloretyl)amin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra N-butyldietanolamin (6 g, 37,2 mmol). Utbytte 11,3 g (99%); hvitt pulver; smp. 165°C; MS: 197,9 (M+H)<+>. l-Butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)eddiksyre-etylester (5 g, 19,38 mmol) og butyl-bis-(2-kloretyl)amin (4,52 g, 19,38 mmol). Utbytte 6,86 g (93%); brun olje; MS: 384 (M+H)<+. >l-Butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra l-butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksyIsyre-etylester (6,42 g, 16,8 mmol) løst i metanol (200 ml) og 10 N NaOH (20 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 1,6 g (27%); hvitt pulver; smp. 206°C; MS: 356,4 (M+H)<+>.
Ved å starte fra l-butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksyl-syre (1,51 g, 4,3 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 200 mg av l-butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt fast stoff. Utbytte 9,3%; smp. 75°C; MS: 371,1 (M+H)<+>;
<!>H NMR (300 MHz, DMSO-d6): 5 0,87 (t, J=7,2 Hz, 3H), 1,27 (m, 2H), 1,59 (m, 2H), 2,27 (m, 2H), 2,45 (m, 2H), 2,50 (m, 2H), 2,65 (m, 2H), 2,97 (m, 2H), 3,88 (s, 3H), 7,18 (d, 2H), 7,69 (d, 2H).
Eksempel 12
l-Cyklooktyl-4-(4-metoksy-benzensulfo
Cyklooktyl-bis-(2-kloretyl)amin ble fremstilt ifølge den generelle fremgangs-måte som vist i eksempel 1, ved å starte fra N-cyklooktyldietanolamin (6 g, 28 mmol). Utbytte 10 g (99%); nesten hvitt fast stoff; smp. 158°C; MS: 251,9 (M+H)<+. >l-Cyklooktyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etyl-ester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (5 g, 19,4 mmol) og cyklooktyl-bis-(2-kloretyl)amin (5,57 g, 19,4 mmol). Utbytte 8,2 g (96%); brun olje; MS: 438 (M+H)<+>. 1 -Cyklooktyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra l-cyklooktyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester (8 g, 18,3 mmol) løst i metanol (200 ml) og 10 N NaOH (25 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 2,36 g (32%); hvitt pulver; smp. 180°C; MS: 410 (M+H)<+>. Ved å starte fra l-cyklooktyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre (2,26 g, 5,53 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 570 mg av l-cyklooktyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hyroksyamid som et hvitt pulver. Utbytte 22%; smp. >200°C; MS: 425 (M+H)<+>; 'H NMR (300 MHz, DMSO-d6): 5 1,42-1,66 (m, 14H), 1,1 (m, 2H), 2,33 (m, 2H), 2,67 (m, 2H), 3,30-3,51 (m, 3H), 3,88 (s, 3H), 7,17 (d, 1H), 7,66 (d, 2H). Eksempel 13 l-Etyl-4-(4-metoksy-benzensuIfonyl)-piperidin-4-karboksylsyre-hydroksyamid l-Etyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksyIsyre-etylesterble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (3 g, 11,6 mmol) og etyl-bis-(2-kloretyl)-amin (2,39 g, 11,6 mmol). Utbytte 3,09 g (75%); lavtsmeltende brunt fast stoff; MS: 356
(M+H)<+>.
l-Etyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra l-etyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester (2,42 g, 6,8 mmol) løst i metanol (100 ml) og 10 N NaOH (15 ml). Den resulterende
reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 1,29 g (58%); hvitt fast stoff; smp. 209°C; MS: 328 (M+H)<+>. Ved å starte fra l-etyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksyl-syre (1,23 g, 3,76 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 1,02 g av l-etyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt pulver. Utbytte 80%; smp. 85°C; MS: 343 (M+H)<+>; 'H NMR (300 MHz, DMSO-de): 6 0,926 (t, J=7,l Hz, 3H), 1,68-1,89 (m, 4H), 2,05-2,24 (m, 4H), 2,73 (q, 2H), 3,85 (s, 3H), 7,07 (d, 2H), 7,64 (d, 2H). Eksempel 14 l-Isopropyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid l-Isopropyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (5,7 g, 22,2 mmol) og isopropyl-bis-(2-kloretyl)amin (4,9 g, 22,2 mmol). Utbytte 5,64 g (68%); lavt-smeltende brunt fast stoff; MS: 370 (M+H)<+>. 1 -Isopropyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra l-isopropyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester (5,6 g, 15,2 mmol) løst i metanol (75 ml) og 10 N NaOH (25 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 2,18 g (42%); hvitt pulver; smp. 204°C; MS: 341,9 (M+H)<+>. Ved å starte fra l-isopropyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre (2,13 g, 6,25 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 590 mg av l-isopropyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid som et hvitt pulver. Utbytte 2,4%; smp. 75°C; MS: 357 (M+H)<+>; 'H NMR (300 MHz, DMSO-de): 6 1,21 (d, J=6,6 Hz, 6H), 2,33-3,53 (m, 9H), 3,88 (s, 3H), 7,16 (d, 2H), 7,66 (d, 2H). Eksempel 15 l-Metyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid l-Metyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylesterble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (3 g, 11,6 mmol) og metyl-bis-(2-kloretyl)amin (2,2 g, 11,6 mmol). Utbytte 3,09 g (75%); lavtsmeltende brunt fast stoff; MS: 342 (M+H)<+>. l-Metyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra l-metyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester (8,7 g, 25,6 mmol) løst i metanol (300 ml) og 10 N NaOH (35 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 3,23 g (41%); hvitt fast stoff; smp. 204°C; MS: 313,9 (M+H)<+>. Ved å starte fra l-metyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre (2,0 g, 6,38 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble isolert 1,10 g av 1-metyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid som et gult pulver. Utbytte 53%; smp. 89°C; MS: 319 (M+H)<+>; 'H NMR (300 MHz, DMSO-d6): 8 1,67-1,76 (m, 2H), 1,85-1,96 (m, 2H), 2,05 (s, 3H), 2,17 (d, J=l 1,4 Hz, 2H), 2,57 (d, J=10,4 Hz, 2H), 3,1 (s, 3H), 7,02 (d, 2H), 7,62 (d, 2H). Eksempel 16 l-Benzyl-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid l-Benzyl-4-(4-butoksy-benzensulfonyI)-piperidin-4-karboksylsyre-etylesterble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(butoksy-benzensulfonyl)-eddiksyre-etylester (6 g, 20 mmol) og bis-2-(kloretyl)benzyI-amin (10 g, 30 mmol). Utbytte 5,15 g (56%); gul olje; MS: 460 (M+H)<+. >l-Benzyl-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra l-benzyl-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester (5,1 g, 11,1 mmol) løst i THF:metanol 3:1 og 10 N NaOH (10 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 2,66 g (56%); nesten hvitt fast stoff; smp. 210°C; MS: 432 (M+H)<+>.
Ved å starte fra l-benzyl-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre (2,61 g, 6,06 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 860 mg av l-benzyl-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt pulver. Utbytte 32%; smp. 144°C; MS: 446,9 (M+H)<+>;
<*>H NMR (300 MHz, DMSO-de): 5 0,94 (t, J=7,3 Hz, 3H), 1,44 (q, J=7,5 Hz, 2H), 1,70 (q, 2H), 2,28-2,32 (m, 2H), 2,50 (d, 2H), 2,74-2,1 (m, 2H), 3,35 (d, 2H), 4,08 (t, J=6,3 Hz,
2H), 4,34 (s, 2H), 7,13 (d, J=8,7 Hz, 2H), 7,45 (s, 3H), 7,54 (s, 2H), 7,74 (d, J=8,7 Hz, 2H), 9,35 (s,lH), 10,7 (s, 1H).
Eksempel 17 l-(4-Fluor-benzyl)-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid l-(4-Fluor-benzyl)-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-erylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (18,8 g, 72,8 mmol) og (4-fluor-benzyl)-bis-(2-kloretyl)amin (20,8 g, 73 mmol). Utbytte 25 g (79%); brun olje; MS: 436,9
(M+H)<+>.
l-(4-Fluor-benzyl)-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyreble fremstilt ved å starte fra l-(4-fluor-benzyl)-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester (17,4 g, 40 mmol) løst i THF:metanol 3:1 og 10 N NaOH (40 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 10,8 g (66%); fargeløst fast stoff; smp. 154°C; MS: 408 (M+H)<+>. Ved å starte fra l-(4-fluor-benzyl)-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre (8,14 g, 20 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 4,3 g av l-(4-fluor-benzyl)-4-(4-metoksy-benzen-sulfonyl)-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt fast stoff. Utbytte 51%; smp. 176-178°C; MS: 484,7 (M+H)<+>; <!>H NMR (300 MHz, DMSO-d6): 5 2,12-2,20 (m, 2H), 2,64-2,79 (m, 2H), 3,32-3,45 (m, 4H), 3,87 (s, 3H), 4,31 (s, 2H), 7,14-7,19 (d, J=17 Hz, 2H), 7,17-7,33 (d, J=8,l Hz, 2H), 7,50-7,54 (d, 2H), 7,65-7,68 (d, 2H), 9,38 (s, 1H), 9,75 (s, 1H). Eksempel 18 l-(4-Fluor-benzyl)-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid l-(4-Fluor-benzyl)-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(butoksy-benzensulfonyl)-eddiksyre-etyIester (6 g, 20 mmol) og (4-fluor-benzyl)-bis-(2-kloretyl)amin (5,73 g, 20 mmol). Utbytte 8,2 g (86%); gul olje; MS: 478
(M+H)<+.>
1- (4-Fluor-benzyl)-4-(4-butoksy-benzensulfonyl)-piperidin-4-karbok^ fremstilt ved å starte fra l-(4-fluor-benzyl)-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre-etylester (4,77 g, 10 mmol) løst i THF:metanol 3:1 og 10 N NaOH (10 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 3,5 g (79%); nesten hvitt fast stoff; smp. 114°C; MS: 450 (M+H)<+>.
Ved å starte fra l-(4-fluor-benzyl)-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre (2,24 g, 5,0 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 200 mg av l-(4-fluor-benzyl)-4-(4-butoksy-benzen-sulfonyl)-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt pulver. Utbytte 9%; smp. 112°C; MS: 465,9 (M+H)<+>;
'H NMR (300 MHz, DMSO-d6): 5 0,94 (t, J=7,3 Hz, 3H), 1,35-1,50 (m, 2H), 1,68-1,77 (m, 2H), 2,20-2,28 (m, 2H), 2,66-2,77 (m, 2H), 3,77-3,78 (m, 4H), 4,06-4,10 (m, 2H), 4,19 (s, 2H), 7,14-7,19 (d, J=8,7 Hz, 2H), 7,27-7,33 (d, 2H), 7,50-7,54 (d, 2H), 7,65-7,68 (d, 2H), 9,34 (s, 1H), 10,55 (s, 1H).
Eksempel 191
4-(4-Metoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksylsyre-hydroksyamid
2- [(2-Hydroksy-etyl)-(4-metoksy-benzyl)amino]etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanolamin (12,0 g, 114 mmol) og 4-metoksybenzylklorid (14,2 g, 100 mmol). Utbytte 17,5 g (77%); gul olje; MS: 226 (M+H).
4-Metoksybenzyl-bis-(2-kloretyl)amin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-metoksy-benzyl-dietanolamin (10 g, 44 mmol). Utbytte 10 g (75%); gult fast stoff; smp. 55°C; MS: 263,1 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksyl-syre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyI)-eddiksyre-etylester (5,0 g, 20 mmol) og bis-(2-kloretyl)-(4-metoksy-benzyl)amin (7,0 g, 22 mmol). Utbytte 5,0 g (56%); lavtsmeltende fast stoff; MS: 448,5 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksyI-syre ble fremstilt ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksylsyre-etylester (4,2 g, 10 mmol) løst i metanol (30 ml), 10N
natriumhydroksyd (10 ml), tetrahydrofuran (20 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 3,0 g (71%); hvitt fast stoff; smp. 190°C; MS: 420,4 (M+H)<+>.
Ved å starte fra 4-(4-metoksy-benzensuIfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksylsyre (2,0 g, 4,7 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 1,2 g av 4-(4-metoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksylsyre-hydroksyamid som et hvitt fast stoff. Smp. 175°C; utbytte 1,2 g, 59%; MS: 433,0 (M+H)<+>;
'H NMR (300 MHz, DMSO-d6): 5 1,8 (m, 4H), 2,3 (m, 2H), 2,73 (m, 2H), 3,37 (d, 2H), 3,76 (s, 3H), 3,88 (s, 3H), 6,87 (d, 2H), 7,11 (d, 2H), 7,21 (d, 2H), 7,65 (d, 2H), 9,2 (bs, 1H), 10,9 (bs, 1H).
Eksempel 20
4-(4-metoksy-benzensulfonyl)-l-[2-(4-metoksyfenyl)-etyl]-piperidin-4-karboksylsyre-hydroksyamid
2-{(2-Hydroksy-etyl)-[2-(4-metoksy-fenyl)-etyl]-amino}etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanolamin (10,0 g, overskudd) og l-(2-kloretyl)-4-metoksybenzen (8,5 g, 50 mmol). Utbytte 11 g (92%); gul olje; MS: 240 (M+H)<+>.
Det tilsvarende diklorid, bis-(2-kloretyl)-(4-metoksyfenyl-2-etyl)amin, ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 2-{(2-hydroksy-etyl)-[2-(4-metoksy-fenyl)-etyl]-amino}etanol (10 g, 41,8 mmol). Utbytte 11 g (95%); brun olje; MS: 277,2 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-l-[2-(4-metoksyfenyl)-etyl]-piperidin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)eddiksyre-etylester (5,0 g, 20 mmol) og bis-(2-kloretyl)-(4-metoksyfenyl-2-etyl)amin (6,4 g, 20 mmol). Utbytte 6,0 g (65%); brun olje; MS: 462,5 (M+H)<+.>
4-(4-Metoksy-benzensulfonyl)-l-[2-(4-metoksyfenyl)-etyl]-piperidin-4-karboksylsyre ble fremstilt ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-[2-(4-metoksyfenyl)-etyl]-piperidin-4-karboksylsyre-etylester (5,0 g, 10,8 mmol) løst i THF:metanol 3:1 og 10 N NaOH (40 ml). Den resulterende reaksjonsblanding ble
opparbeidet som vist i eksempel 1. Utbytte 4,0 g (85%); nesten hvitt pulver; smp. 205°C; MS: 434,5 (M+H)<+>.
Ved å starte fra4-(4-metoksy-benzensulfonyl)-l-[2-(4-metoksyfenyl)-etyl]-piperidin-4-karboksylsyre (1,5 g, 3,46 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 900 mg av 4-(4-metoksy-benzensulfonyl)-l-[2-(4-metoksyfenyl)-etyl]-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt fast stoff. Utbytte 58%; smp. 206°C (HC1); MS: 449,5 (M+H)<+>;
<]>H NMR (300 MHz, DMSO-d6): 8 2,3 (m, 2H), 2,5 (m, 3H), 2,8 (m, 2H), 2,95 (m, 2H), 3,25 (m, 2H), 3,4 (m, 4H), 3,60 (d, J=12,3 Hz, 2H), 3,77 (s, 3H), 3,99 (s, 3H), 6,9 (d, 2H), 7,1-7,25 (q, 4H), 7,7 (d, 2H), 9,3 (s, 1H), 10,6 (s, 1H).
Eksempel 21
4-(4-Metoksy-benzensulfonyl)-l-(2-fenyl-etyl)-piperidin-4-karboksylsyre-hydroksyamid
2-[(2-Hydroksy-etyl)-(2-fenyletyl)amino]etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanolamin (6,0 g, 57 mmol) og 2-brometylbenzen (9,0 g, 48,3 mmol). Utbytte 9 g (90%); gul olje; MS: 210 (M+H)<+.>
Bis-(2-kloretyl)-(2-fenyletyl)amin ble fremstilt ifølge den generelle fremgangs-måte som vist i eksempel 1, ved å starte fra 2-[(2-hydroksy-etyl)-(2-fenyletyl)amino]-etanol (8,5 g, 40,6 mmol). Utbytte 11 g (95%); brun olje; MS: 247,1 (M+H)<+.>
4-(4-Metoksy-benzensulfonyl)-l-(2-fenyletyl)-piperidin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (5,0 g, 20 mmol) og bis-(2-kloretyl)-(2-fenyletyl)amin (5,6 g, 20 mmol). Utbytte 5,5 g (63%); brun olje; MS: 432,5 (M+H)<+>.
4-(4-Metoksy-benzensuIfonyl)-l-(2-fenyletyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-(2-fenyletyl)-piperidin-4-karboksylsyre-etylester (3,0 g, 6,9 mmol) løst i THF:metanol 3:1 og 10 N NaOH (40 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 2,0 g (72%); nesten hvitt pulver; smp. 208°C; MS: 404,5 (M+H)<+>.
Ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-(2-fenyletyl)-piperidin-4-karboksylsyre (1,5 g, 3,7 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 900 mg av 4-(4-metoksy-benzensulfonyl)-l-(2-fenyl-etyl)-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt fast stoff. Utbytte 58%; smp. 205°C (HC1); MS: 419,4 (M+H)<+>;
<J>H NMR (300 MHz, DMSO-d*): 5 2,3 (m, 2H), 2,5 (m, 3H), 2,8 (m, 2H), 2,95 (m, 2H), 3,25 (m, 2H), 3,4 (m, 4H), 3,9 (s, 3H), 7,22-7,8 (m, 9H), 10,6 (s, 1H), 11,2 (bs, 1H).
Eksempel 22
4-(4-n-Butoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksylsyre-hydroksyamid
4-(4-n-Butoksy-benzensulfony 1)-1-(4-m etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(n-butoksy-benzensulfonyl)-eddiksyre-etylester (2,5 g, 10 mmol) og bis-(2-kloretyl)-(4-metoksy-benzyl)amin (3,0 g, 10 mmol). Utbytte 3,5 g (71%); lavtsmeltende fast stoff; MS: 490,5 (M+H)<+>.
4-(4-n-Butoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksyl-syre ble fremstilt ved å starte fra4-(4-butoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksylsyre-etylester (3,0 g, 6,1 mmol) løst i metanol (30 ml), 10N natriumhydroksyd (10 ml), tetrahydrofuran (20 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 1,5 (53%); hvitt fast stoff; smp. 207°C; MS: 462,5 (M+H)<+>.
Ved å starte fra 4-(4-n-butoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksylsyre (1,0 g, 2,1 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 1,2 g av 4-(4-butoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksylsyre-hydroksyamid som et hvitt fast stoff. Smp. 173°C (HC1); utbytte 800 mg, 77%; MS: 477,5 (M+H)<+>;
'H NMR (300 MHz, DMSO-dé): 8 0,9 (t, 3H), 1,4 (m, 2H), 1,7 (m, 2H), 2,3 (m, 2H), 2,5 (m, 2H), 2,7 (m, 2H), 3,3 (m, 2H), 3,5 (m, 2H), 4,1 (t, 2H), 4,3 (m, 2H), 6,97 (d, 2H), 7,14 (d, 2H), 7,48 (d, 2H), 7,7 (d, 2H), 9,4 (bs, 1H), 10,9 (bs, 1H).
Eksempel 23
4-(4-Metoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksyIsyre-hydroksyamid
2-[(2-Hydroksy-etyl)-(3-fenoksy-propyl)-amino]-etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanolamin (15,8 g, 151 mmol) og 3-fenoksypropylbromid (21,5 g, 100 mmol). Utbytte 21,31 g (95%); gul olje; MS: 238,1 (M+H)<+>.
Bis-(2-kloretyl)-(3-fenoksy-propy])amin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 2-[(2-hydroksy-etyl)-(3-fenoksy-propyl)amino]etanol (20,0 g, 84 mmol). Utbytte 24,0 g (91%); brun olje; MS: 277,8
(M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksyl-syre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (5,2 g, 20 mmol) og bis-(2-kloretyl)-(3-fenoksy-propyl)amin (7,0 g, 22 mmol). Utbytte 6,5 g (70%); brun olje; MS: 462,5 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-1 -(3-fenoksy-propyl)-piperidin-4-karboksyl-syre ble fremstilt ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksylsyre-etylester (4,2 g, 9,1 mmol) løst i THF:metanol 3:1 og 10 N NaOH (40 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 3,0 g (75%); nesten hvitt pulver; smp. 195°C; MS: 434,5 (M+H)<+>.
Ved å starte fra4-(4-metoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksylsyre (2,5 g, 5,77 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 1,2 g av 4-(4-metoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt fast stoff. Utbytte 46%; smp. 101°C; MS: 448.5 (M+H)<+>;
<*>H NMR (300 MHz, DMSO-de): 8 2,18 (m, 2H), 2,3 (m, 2H), 2,58 (m, 2H), 2,6-2,73 (m, 2H), 3,0-3,06 (m, 2H), 3,60 (m, 2H), 3,87 (s, 3H), 4,01 (t, 2H), 6,9-7,7 (m, 9H), 9,33 (bs, 1H), 10,28 (bs, 1H).
Eksempel 24
4-(4-n-Butoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksylsyre-hydroksyamid
4-(4-n-Butoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksyl-syre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(butoksy-benzensulfonyl)-eddiksyre-etylester (3,0 g, 10 mmol) og bis-(2-kloretyl)-(3-fenoksy-propyl)amin (3,0 g, 11 mmol). Utbytte 4,5 (89%); brun olje; MS: 504.6 (M+H)<+>.
4-(4-n-Butoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksyl-syre ble fremstilt ved å starte fra 4-(4-n-butoksy-benzensuIfonyl)-l-(3-fenoksy-propyl)-
piperidin-4-karboksyIsyre-etylester (4,0 g, 7,9 mmol) løst i THF:metanol 3:1 og 10 N NaOH (40 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 3,0 g (79%); nesten hvitt pulver; smp. 191°C; MS: 476,5 (M+H)<+>.
Ved å starte fra4-(4-n-butoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksylsyre (700 mg, 1,4 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 300 mg av 4-(4-n-butoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt fast stoff. Utbytte 43%; smp. 84°C; MS: 491,5 (M+H)<+>;
<!>H NMR (300 MHz, DMSO-de): 8 0,9 (t, 3H), 1,5 (m, 2H), 1,8 (m, 2H), 2,18 (m, 2H), 2,3 (m, 2H), 2,58 (m, 2H), 2,6-2,73 (m, 2H), 3,2 (m, 2H), 3,40 (m, 6H), 3,97 (t, 1H), 4,1 (t, 2H), 6,9-7,7 (m, 9H), 10,7 (bs, 1H), 11,28 (bs, 1H).
Eksempel 25
4-(4-Metoksy-benzensulfonyl)-l-(2-fenoksy-etyl)-piperidin-4-karboksylsyre-hydroksyamid
2-[(2-Hydroksy-etyl)-(2-fenoksyetyl)amino]etanol ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanolamin (15,0 g, 150 mmol) og 2-kIorfenol (15,6 g, 100 mmol). Utbytte 18 g (80%); fargeløs olje; MS: 226 (M+H)<+>.
Bis-(2-kloretyl)-(2-fenoksyetyl)amin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 2-[(2-hydroksy-etyl)-(2-fenoksyetyl)amino]etanol (20,0 g, 88,8 mmol). Utbytte 25 g (94%); brun olje; MS: 263,1
(M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-l-(2-fenoksy-etyl)-piperidin-4-karboksylsyre-etylesterble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (5,0 g, 20 mmol) og bis-(2-kloretyl)-(2-fenoksyetyl)amin (6,0 g, 20 mmol). Utbytte 5,8 g (64%); brun olje; MS: 448,5
(M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-1 -(2-fenoksy-etyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-(2-fenyl-etoksy)-piperidin-4-karboksylsyre-etyleter (5,0 g, 11,1 mmol) løst i THF:metanol 3:1 og 10 N NaOH (40 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 3,0 g (63%); nesten hvitt pulver; smp. 235°C; MS: 420,5 (M+H)<+>.
Ved å starte fra 4-(4-metoksy-benzensulfonyl)-l-(2-fenoksy-etyl)-piperidin-4-karboksylsyre (2,5 g, 5,9 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 1,3 g av 4-(4-metoksy-benzensulfonyl)-l-(2-fenoksy-etyl)-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt fast stoff. Utbytte 50%; smp. 168-172°C (HC1); MS: 435,4 (M+H)<+>;
'H NMR (300 MHz, DMSO-d6): 8 2,3 (m, 2H), 2,5 (m, 2H), 2,9 (m, 2H), 3,4 (m, 4H), 3,5 (m, 2H), 3,7 (m, 2H), 3,9 (s, 3H), 4,4 (m, 2H), 6,9-7,8 (m, 9H), 9,3 (s, 1H), 10,2 (bs, 1H), 11,3 (s, 1H).
Eksempel 26
4-(4-n-Butoksy-benzensulfonyl)-l-(2-fenoksy-etyI)-piperidin-4-karboksylsyre-hydroksyamid
4-(4-Butoksy-benzensulfonyl)-l-(2-fenoksy-etyl)-piperidin-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddiksyre-etylester (2,5 g, 10 mmol) og bis-(2-kloretyl)-(2-fenoksy-etyl)amin (2,98 g, 10 mmol). Utbytte 3,0 g (69%); brun olje; MS: 490,6 (M+H)<+>.
4-(4-n-Butoksy-benzensulfonyl)-1 -(2-fenoksy-etyl)-piperidin-4-karboksylsyre ble fremstilt ved å starte fra 4-(4-n-butoksy-benzensulfonyl)-l-(2-fenyletoksyl)-piperidin-4-karboksylsyre-etylester (2,5 g, 5,76 mmol) løst i THF:metanol 3:1 og 10 N NaOH (40 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 1,5 g (56%); nesten hvitt pulver; smp. 204°C; MS: 462,5 (M+H)<+>.
Ved å starte fra 4-(4-n-butoksy-benzensulfonyl)-l-(2-fenoksy-etyl)-piperidin-4-karboksylsyre (1,0 g, 2,16 mmol) og ved å følge fremgangsmåten som vist i eksempel 1, ble det isolert 600 mg av 4-(4-butoksy-benzensuIfonyl)-l-(2-fenoksy-etyl)-piperidin-4-karboksylsyre-hydroksyamid som et nesten hvitt fast stoff. Utbytte 58%; smp. 1120°C (HC1); MS: 477,4 (M+H)<+>;
<!>H NMR (300 MHz, DMSO-d6): 8 0,942 (t, 3H), 1,4 (m, 2H), 1,7 (m, 2H), 2,3 (m, 2H), 2,5 (m, 4H), 2,8 (m, 2H), 2,9-3,4 (m, 4H), 3,3 (m, 4H), 4,2 (t, 2H), 4,4 (m, 2H), 6,9-7,7 (m, 9H), 9,4 (s, 1H), 10,5 (bs, 1H), 11,3 (s, 1H).
Eksempel 27
4-(4-Metoksy-benzensulfonyl)-l-[4-(2-piperidin-l-yl-etoksy karboksylsyre-hydroksyamid
Bis-(2-kloretyl)-[4-(2-piperidin-l-yI-etoksy)-benzyl]-amin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra dietanol-amin (15,0 g, 150 mmol) og 4-(2-pipeirdin-l-yl-etoksy)benzylklorid (5,9 g, 20 mmol). Utbytte 5,5 g (85%); brunt halvfast stoff; MS: 323 (M+H)<+>.
Bis-(2-kloretyl)-[4-(2-piperidin-l-yl-etoksy)-benzyl]amin ble fremstilt ifølge den generelle fremgangsmåte som vist i eksempel 1, ved å starte fra 2-[(2-hydroksy-etyl)-[4-(2-piperidin-l-yl-etoksy)benzyl]amin (3,22 g, 10 mmol). Utbytte 4,0 g (92%); brunt halvfast stoff; MS: 361,1 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-l-[4-(2-piperidin-l-yl-etoksy)-benzyl]-piperidin-e-4-karboksylsyre-etylester ble fremstilt ifølge den generelle fremgangs-måte som vist i eksempel 1, ved å starte fra 4-(metoksy-benzensulfonyl)-eddik-syre-etylester (5,0 g, 20 mmol) og bis-(2-kloretyl)-[4-(2-pipeirdin-l-yl-etoksy)-benzyl]amin (8,6 g, 20 mmol). Utbytte 6,0 g (55%); brun olje; MS: 545,7 (M+H)<+>.
4-(4-Metoksy-benzensulfonyl)-l-[4-(2-piperidin-l-yl-etoksy)-benzyl]-piperidin-4-karboksylsyre ble fremstilt ved å starte fra 4-(4-metoksy-benzen-sulfonyl)-l-[4-(2-piperidin-l-yl-etoksy)-benzyl]-piperidin-4-karboksylsyre-etylester (5,4 g, 10 mmol) løst i THF:metanol 3:1 og 10 N NaOH (40 ml). Den resulterende reaksjonsblanding ble opparbeidet som vist i eksempel 1. Utbytte 4,0 g (77%); nesten hvitt pulver; smp. 174°C; MS: 517,6 (M+H)<+>.
Ved å starte fra4-(4-metoksy-benzensulfonyl)-l-[4-(2-piperidin-l-yl-etoksy)-benzyl]-piperidin-e-4-karboksylsyre (3,5 g, 6,78 mmol) og ved å følge fremgangs-måten som vist i eksempel 1, ble det isolert 1,8 g av 4-(4-metoksy-benzen-sulfonyl)-l-[4-(2-piperidin-l-yl-etoksy)-benzyl]-pipeirdin-e-4-karboksylsyre-hydroksyamid som et blekgult fast stoff. Utbytte 49%; smp. 114°C (HC1); MS: 532 (M+H)<+>;
<l>H NMR (300 MHz, DMSO-de): 5 1,4-1,6 (m, 4H), 1,9 (m, 2H), 2,3 (m, 2H), 2,8 (m, 2H), 3,4 (m, 4H), 3,9 (s, 3H), 4,2 (m, 1H), 6,9-7,8 (m, 8H), 9,1 (s, 1H), 10,8 (bs, 1H).
De aktuelle forbindelser ifølge den foreliggende oppfinnelse ble testet for biologisk aktivitet etter følgende fremgangsmåter.
In vitro-gelatinaseanalyse
Denne analyse er basert på spaltingen av tiopeptidsubstratet ((Ac-Pro-Leu-Gly(2 merkapto-4-metyl-pentanoyl)-Leu-Gly-Oet), Bachem Bioscience) med enzymet, gelatinase, under frigjøring av substratproduktet som reagerer kolorimetrisk med DTNB ((5,5'-ditio-bis(2-nitro-benzosyre)). Enzymaktiviteten blir målt ved hastigheten av fargeøkning.
Tiopeptidsubstratet lages opp friskt som en 20 mM stokkløsning i 100% DMSO, og DTNB løses i 100% DMSO som en 100 mM stokkløsning og lagres i mørke ved romtemperatur. Både substratet og DTNB blir fortynnet sammen til 1 mM med substratbuffer (50 mM HEPES pH 7,5,5 mM CaCl2) før anvendelse. Stokkløsningen av human neutrofil gelatinase B fortynnes med analysebuffer (50 mM HEPES pH 7,5, 5 mM CaCh, 0,02% Brij) til en sluttkonsentrasjon på 0,15 nM.
Analysebufferen, enzymet, DTNB/substrat (500 uM sluttkonsentrasjon) og bærer eller inhibitor tilsettes til en 96-brønners plate (samlet reaksjonsvolum på 200 ul), og økningen i fargen blir overvåket spektrofotometrisk i 5 minutter ved 405 nm på en plateleser.
Økningen i OD405 blir avsatt, og helningen av linjen som representerer reaksjonshastigheten blir beregnet.
Lineariteten av reaksjonshastigheten blir bekreftet (r2 >0,85). Gjennom-snittet (x + sem) av kontrollhastigheten blir beregnet og sammenlignet for statistisk signifikans (p
<0,05) med medikamentbehandlede hastigheter ved anvendelse av Dunnett's multiple sammenligningstest. Dose-responsforhold kan genereres ved anvendelse av multiple doser av medikament, og lCso-verdier med 95% Cl, blir anslått ved anvendelse av lineær regresjon (IPRED, HTB).
Referanser: Weingarten, H og Feder, J., Spectrophotometric assay for vertebrate kollagenase, Anal. Biochem. 147,437-440 (1985).
In vitro-kollagenaseanalyse
Denne analyse er basert på spaltingen av et peptidsubstrat ((Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMa)-NH2), Peptide International, Inc.) ved at kollagenase frigjør den fluorescerende NMa-gruppe som blir kvantifisert på fluoro-meteret. Dnp vil undertrykke NMa-fluorescensen i det intakte substrat. Analysen kjøres i HCBC-analysebuffer (50 mM HEPES, pH 7,0, 5 mM Ca<+2>, 0,02% Brij, 0,5% cystein), med human rekombinant fibroblastkollagenase (avkortet, mw = 18.828, W AR, Radnor). Substratet løses i metanol og lagres i frossen tilstand i 1 mM alikvoter. Kollagenase blir lagret frossen i buffer i 25 uM alikvoter. For analysen, blir substrat løst i HCBC-buffer til en sluttkonsentrasjon på 10 uM og kollagenase til en sluttkonsentrasjon på 5 nM. Forbindelsene løses i metanol, DMSO eller HCBC. Metanolen og DSMO blir fortynnet i HCBC til <1,0%. Forbindelsene tilsettes til 96-brønners platen inneholdende enzym, og reaksjonen startes ved tilsetning av substrat.
Reaksjonen avleses (eksitasjon 340 nm, emisjon 444 nm) i 10 minutter, og økningen i fluorescens over tiden blir avsatt som en lineær linje. Helningen av linjen beregnes og representerer reaksjonshastigheten.
Lineariteten av reaksjonshastigheten blir bekreftet (r2 >0,85). Gjennom-snittet (x + sem) av kontrollhastigheten blir beregnet og sammenlignet for statistisk signifikans (p
<0,05) med medikamentbehandlede hastigheter ved anvendelse av Dunnetfs multiple sammenligningstest. Dose-responsforhold kan genereres ved anvendelse av multiple doser av medikament, og lCso-verdier med 95% Cl, blir anslått ved anvendelse av lineær regresjon (IPRED, HTB).
Referanser: Bickett, D.M. et al., A high throughput fluorogenic substrate for interstitial collagenase (MMP-1) and gelatinase (MMP-9), anal. Biochem. 212, 58-64 (1993).
Fremgangsmåte for måling av TACE-inhibering
Ved anvendelse av 96-brønners svarte mikrotiterplater, får hver brønn en løsning sammensatt av 10 ul TACE (Immunex, sluttkonsentrasjon 1 ug/ml), 70 ul Tris-buffer, pH 7,4, inneholdende 10% glycerol (sluttkonsentrasjon 10 mM), og 10 ul av testforbindelse-løsning i DMSO (sluttkonsentrasjon 1 uM, DMSO-konsentrasjon <1%) og inkuberes i 10 minutter ved romtemperatur. Reaksjonen initieres ved tilsetning av et fluorescerende peptidylsubstrat (sluttkonsentrasjon 100 uM) til hver brønn og deretter rysting på en rystemaskin i 5 sekunder. Reaksjonen avleses (eksitasjon 340 nm, emisjon 420 nm) i 10 minutter, og økningen i fluorescens over tiden, blir avsatt som en lineær linje. Helningen av linjen blir beregnet, og representerer reaksjonshastigheten.
Lineariteten av reaksjonshastigheten blir bekreftet (r2 >0,85). Gjennom-snittet (x + sem) av kontrollhastigheten blir beregnet og sammenlignet for statistisk signifikans (p
<0,05) med medikamentbehandlede hastigheter ved anvendelse av Dunnetfs multiple sammenligningstest. Dose-responsforhold kan genereres ved anvendelse av multiple doser
av medikament, og lCso-verdier med 95% Cl, blir anslått ved anvendelse av lineær regresjon.
Resultatene oppnådd ved å følge disse standard eksperimentelle testfrem-gangsmåter, er presentert i følgende tabell.
IC 50 (nM eller % inhibering ved 1 mikromolar)
Farmasøytisk blanding
Forbindelser ifølge denne oppfinnelse kan administreres rene eller med en farmasøytisk bærer til en pasient behov derfor. Den farmasøytiske bærer kan være fast eller flytende.
Anvendelige faste bærere kan inkludere én eller flere substanser som også kan virke som smaksmidler, smøremidler, solubilisatorer, suspensjonsmidler, fyllstoffer, glidemidler, kompresjonshjelpemidler, bindemidler eller tablett-disintegreringsmidler eller som innkapslingsmateriale. I pulvere, vil bæreren være et fint oppdelt fast stoff som er i blanding med den fint oppdelte aktive bestanddel. I tabletter, blir den aktive bestanddel blandet med bæreren som har de nødvendige kompresjonsegenskaper i egnede forhold og kompaktert i den ønskede form og størrelse. Pulverne og tablettene inneholder fortrinnsvis opp til 99% av den aktive bestanddel. Egnede faste bærere inkluderer for eksempel kalsiumfosfat, magnesiumstearat, talk, sukkere, laktose, dekstrin, stivelse, gelatin, cellulose, metylcellulose, natriumkarboksymetylcellulose, polyvinylpyrrolidin, lavt-smeltende vokser og ionebytterharpikser.
Flytende bærere kan anvendes til fremstilling av løsninger, suspensjoner, emulsjoner, siruper og eliksirer. Den aktive bestanddel ifølge denne oppfinnelse, kan være løst eller oppslemmet i en farmasøytisk akseptabel flytende bærer så som vann, et organisk løsningsmiddel, en blanding av begge eller farmasøytisk akseptable oljer eller fett. Den flytende bærer kan inneholde andre egnede farmasøytiske additiver slik som solubilisa-orer, emulgeringsmidler, buffere, konserveringsmidler, søtemidler, smaksmidler, suspensjonsmidler, fortyknings-midler, fargestoffer, viskositetsregulatorer, stabilisatorer eller osmo-regulatorer. Egnede eksempler på flytende bærere for oral eller parenteral administrering inkluderer vann (spesielt inneholdende additiver som ovenfor, for eksempel cellulosederivater, fortrinnsvis natriumkarboksymetylcellulose-løsning), alkoholer (innbefattet énverdige alkoholer og flerverdige alkoholer, for eksempel glykoler) og deres derivater, og oljer (for eksempel fraksjonert kokosnøttolje og arakisolje). For parenteral administrering, kan bæreren også være en oljeester så som etyloleat og isopropylmyristat. Sterile flytende bærere anvendes i sterile blandinger i flytende form for parenteral administrering.
Flytende farmasøytiske blandinger som er sterile løsninger eller suspensjoner, kan anvendes ved for eksempel intramuskulær, intraperitoneal eller subkutan injeksjon. Sterile løsninger kan også administreres intravenøst. Oral administrering kan være i form av enten flytende eller fast blanding.
Forbindelsene ifølge denne oppfinnelse kan administreres rektalt i form av en konvensjonell stikkpille. For administrering ved intranasal eller intrabronkial inhalasjon eller innblåsing, kan forbindelsene ifølge denne oppfinnelse formuleres til en vandig eller delvis vandig løsning, som deretter kan anvendes i form av en aerosol. Forbindelsene ifølge denne oppfinnelse kan også administreres transdermalt ved anvendelse av et transdermalt plaster innehold-ende den aktive forbindelse, og en bærer som er inert overfor den aktive forbind-else, er ikke-toksisk overfor huden, og tillater avgivelse av middelet for systemisk absorpsjon i blodstrømmen via huden. Bæreren kan ha et hvilket som helst antall former så som kremer og salver, pastaer, geler og okklusive anordninger. Kremene og salvene kan være viskøse, flytende eller halvfaste emulsjoner av enten olje i vann eller vann i olje-typen. Pasta sammensatt av absorberende pulvere dispergert i petroleum eller hydrofil petroleum inneholdende den aktive bestanddel, kan også være egnet. Flere forskjellige okklusive anordninger kan anvendes til å frigjøre den aktive bestanddel til blodstrømmen, slik som en semi-permeabel membran som dekker et reservoir inne-oldende den aktive bestanddel med eller uten en bærer, eller en matriks inneholdende den aktive bestanddel. Andre okklusive anordninger er kjent i litteraturen.
Den dosering som skal anvendes ved behandling av en bestemt pasient som lider av en sykdom eller tilstand hvori MMP'er og TACE er involvert, må bestemmes subjektivt av den ansvarlige lege. De involverte variabler inkluderer alvorlighetsgraden av dysfunk-jonen, og pasientens størrelse, alder og respons-mønster. Behandlingen vil vanligvis bli startet med små doseringer mindre enn den optimale dose av forbindelsen. Deretter blir doseringen øket inntil den optimale effekt under omstendighetene blir nådd. Nøyaktige doseringer for oral, parenteral, nasal eller intrabronkial administrering vil bli bestemt av den administrerende lege basert på erfaring med det enkelte individ som behandles og standardmedisinske prinsipper.
Fortrinnsvis vil den farmasøytiske blanding være i enhetsdoseirngsform, for eksempel som tabletter eller kapsler. I slik form, blir blandingen oppdel i enhets-doser
inneholdende hensiktsmessige mengder av den aktive bestanddel; enhets-doseirngsformen kan være emballerte blandinger, for eksempel innpakkede pulvere, medisinglass, ampuller, forhåndsfylte sprøyter eller småposer innehold-ende væsker. Enhetsdoseringsformen kan for eksempel være selve kapselen eller tabletten, eller den kan være det hensiktsmessige antall av hvilke som helst slike blandinger i pakningsform.
Claims (17)
1. Forbindelse, karakterisert ved formel 1
hvori R<1> er fenyl, eventuelt substituert med Ci-C6-alkoksy;
A er -S-, -SO- eller S02-;
R<2> og R<3>, sammen med det karbonatom som de er bundet til, danner en piperidinring som eventuelt er N-substituert med en gruppe valgt fra: fenyl-Ci-Gr alkyl (som igjen kan være substituert med Ci-C6-alkoksy, halogen, Ci-C6-alkyl eller piperidyl-Ci-Ce-alkoksy), naftyl, bifenyl-C]-C6-alkyl, C2-Cio-alkenyl, Ci-Cg-alkyl, C4-Cio-cykloalkyl eller fenoksy-Ci-C6-alkyl;
R<4> er hydrogen;
eller et farmasøytisk akseptabelt salt derav.
2. Forbindelse ifølge krav 1, karakterisert ved at den er 1 -benzyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid eller et farmasøytisk akseptabelt salt derav.
3. Forbindelse ifølge krav 1, karakterisert ved at den er 4-(4-metoksy-benzensulfonyl)-1 -(3-metoksy-benzyl)-piperidin-4-karboksylsyre-hydroksyamid eller et farmasøytisk akseptabelt salt derav.
4. Forbindelse ifølge krav 1, karakterisert ved at den er 1 -(3,4-diklorbenzyl)-4-(4-metoksy-berizen-sulfonyl)-piperidin-4-karboksylsyre-hydroksyamid eller et farmasøytisk akseptabelt salt derav.
5. Forbindelse ifølge krav 1, karakterisert ved at den er 4-(4-metoksy-benzensulfonyl)-l -(4-metyl-benzyl)-piperidin-4-karboksylsyre-hydroksyamid eller et farmasøytisk akseptabelt salt derav.
6. Forbindelse ifølge krav 1, karakterisert ved at den er 4-(4-metoksy-benzensulfonyl)-1 -naftalen-2-yl-metylpiperidin-4-karboksylsyre-hydroksyamid eller et farmasøytisk akseptabelt salt derav.
7. Forbindelse ifølge krav 1, karakterisert ved at den er l-bifenyl-4-ylmetyl-4-(4-metoksy-benzen-sulfonyl)-piperidin-4-karboksylsyre-hydroksyamid eller et farmasøytisk akseptabelt salt derav.
8. Forbindelse ifølge krav 1, karakterisert ved at den er 4-(4-metoksy-benzensulfonyl)-l -(3-metyl-but-2-enyl)-piperidin-4-karboksylsyre-hydroksyamid eller et farmasøytisk akseptabelt salt derav.
9. Forbindelse ifølge krav 1, karakterisert ved at den er l-(4-brom-benzyl)-4-(4-metoksy-benzen-sulfonyl)-pipeirdin-4-karboksylsyre-hydroksyamid eller et farmasøytisk akseptabelt salt derav.
10. Forbindelse ifølge krav 1, karakterisert ved at den er 4-(4-metoksy-benzensulfonyl)-1 -[4-(2-piperidin-1 -yl-etoksy)-benzyl]-pipeirdin-4-karboksylsyre-hydroksyamid eller et farmasøytisk akseptabelt salt derav.
11. Forbindelse ifølge krav 1 eller et farmasøytisk akseptabelt salt derav, karakterisert ved at de er valgt fra gruppen av forbindelser bestående av: 4-(4-metoksy-benzensulfonyl)-l-(3-fenyl-propyl)-piperidin-4-karboksylsyre-hydroksyamid, l-tert-butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-butyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-cyklooktyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-etyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-isopropyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-metyl-4-(4-metoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-benzyl-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-(4-fluor-benzyl)-4-(4-metoksy-benzensuIfonyl)-piperidin-4-karboksylsyre-hydroksyamid, l-(4-fluor-benzyl)-4-(4-butoksy-benzensulfonyl)-piperidin-4-karboksylsyre-hydroksyamid, 4-(4-metoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-pipeirdin-4-karboksylsy^ amid, 4-(4-metoksy-benzensulfonyl)-l-[2-(4-metoksyfenyl)-etyl]-piperidin-4-karboksyl-syre-hydroksyamid, 4-(4-metoksy-benzensulfonyl)-l-(2-fenyl-etyl)-piperidin-4-k^ 4-(4-n-butoksy-benzensulfonyl)-l-(4-metoksy-benzyl)-piperidin-4-karboksylsyre-hydroksy-amid, 4-(4-metoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidm^ amid, 4-(4-n-butoksy-benzensulfonyl)-l-(3-fenoksy-propyl)-piperidin-4-karboksylsyre-hydroksy-amid, 4-(4-metoksy-benzensulfonyl)-l-(2-fenoksy-etyl)-piperidin-4-karboksylsyre-hydroksyamid, 4-(4-n-butoksy-benzensulfonyl)-l-(2-fenyl-etyl)-pipeirdin-4-karboksylsyre-hydroksya^ og 4-(4-metoksy-benzensulfonyl)-l-[4-(2-piperidin-l-yl-etoksy)-benzyl]-piperidin-4-karboksyl-syre-hydroksyamid.
12. Anvendelse av en terapeutisk effektiv mengde av en matriksmetalloproteinase-inhiberende forbindelse med formelen
hvori R<1> er fenyl, eventuelt substituert med Ci-Ce-alkoksy;
A er -S-, -SO- eller S02-;
R<2> og R<3>, sammen med det karbonatom som de er bundet til, danner en piperidinring som eventuelt er N-substituert med en gruppe valgt fra: fenyl-Ci-C4-alkyl (som igjen kan være substituert med Ci-Ce-alkoksy, halogen, Ci-Ce-alkyl eller piperidyl-Ci-Ce-alkoksy), naftyl, bifenyl-Ci-Ce-alkyl, C2-Cio-alkenyl, Ci-Cg-alkyl, Q-Cio-cykloalkyl eller fenoksy-Ci-C6-alkyl;
R<4> er hydrogen;
eller et farmasøytisk akseptabelt salt derav for fremstilling av et farmasøytisk preparat
for inhibering av patologiske forandringer formidlet av matriksmetalloproteinaser i pattedyr.
13. Anvendelse ifølge krav 12, idet den behandlede tilstand er aterosklerose, aterosklerotisk plakkdannelse, reduksjon av koronar trombose fra aterosklerotisk plakk-sprengning, restenose, MMP-befordret osteopeni, inflammatoriske sykdommer i sentralnervesystemet, aldring av hud, angiogenese, tumormetastase, tumorvekst, osteoartritt, reumatoid artritt, septisk artritt, sårdannelse i hornhinnen, unormal sårheling, bensykdom, proteinuri, aneurysmal aortasykdom, degenerativt brusktap etter traumatisk leddskade, demyelinerende sykdommer i nervesystemet, skrumplever, glomerulær sykdom i nyrene, for tidlig sprengning av fostermembraner, inflammatorisk tarmsykdom eller periodontal sykdom.
14. Anvendelse ifølge krav 12, idet den behandlede tilstand er aldersrelatert makulær degenerasjon, diabetisk retinopati, proliferativ vitreoretinopati, retinopati ved for tidlig fødsel, øyebetennelse, keratokonus, Sjøgrens syndrom, nærsynthet, øyetumorer, angiogenese/ neovaskularisering av øyet og avstøtning av hornhinneimplantat.
15. Anvendelse av en terapeutisk effektiv mengde av en TACE-inhiberende forbindelse med formelen
hvori R<1> er fenyl, eventuelt substituert med én eller to grupper
uavhengig valgt fra R<5>;
cykloalkyl med 3 til 8 karbonatomer, eventuelt substituert med Ci-C6alkoksy;
A er -S-, -SO- eller S02-;
R og RJ, sammen med det karbonatom som de er bundet til, danner en piperidinring som eventuelt er N-substituert med en gruppe valgt fra: fenyl-Ci-C4-alkyl (som kan være substituert med CrC6-alkoksy, halogen, Ci-Cs-alkyl eller piperidyl-Ci-Ce-alkoksy), naftyl, bifenyl-Ci-C6-alkyl, C2-Cio-alkenyl, Cj-Cg-alkyl, C4-Cio-cykloalkyl eller fenoksy-Ci-Ce-alkyl;
R<4> er hydrogen;
eller et farmasøytisk akseptabelt salt derav for fremstilling av et farmasøytisk preparat for inhibering av patologiske forandringer formidlet av TNF-cc-omdannende enzym (TACE) i pattedyr.
16. Anvendelse ifølge krav 12, idet den behandlede tilstand er reumatoid artritt, avstøtning av implantat, kakeksi, anoreksi, betennelse, feber, insulinresistens, septisk sjokk, kongestiv hjertesvikt, betennelsessykdom i sentralnervesystemet, inflammatorisk tarmsykdom eller HIV-infeksjon.
17. Farmasøytisk blanding, karakterisert ved at den omfatter en farmasøytisk bærer og en terapeutisk effektiv mengde av en matriksmetalloproteinase eller TACE-inhiberende forbindelse ifølge formelen
hvori R<1> er fenyl, eventuelt substituert med én eller to grupper
uavhengig valgt fra R<5>;
cykloalkyl med 3 til 8 karbonatomer, eventuelt substituert med Ci-C6alkoksy;
A er -S-, -SO- eller S02-;
R og R, sammen med det karbonatom som de er bundet til, danner en piperidinring som eventuelt er N-substituert med en gruppe valgt fra: fenyl-Ci-C4-alkyl (som kan være substituert med Ci-C6-alkoksy, halogen, Ci-C6-alkyl eller piperidyl-Ci-Ce-alkoksy), naftyl, bifenyl-Ci-Cg-alkyl, C2-Cio-alkenyl, Cj-Cg-alkyl, C4-Cio-cykloalkyl eller fenoksy-Cj-Ce-alkyl;
R<4> er hydrogen;
eller et farmasøytisk akseptabelt salt derav.
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BR9813069A (pt) * | 1997-10-15 | 2000-08-22 | American Home Prod | Arilóxi-alquil-dialquilaminas |
US6005102A (en) | 1997-10-15 | 1999-12-21 | American Home Products Corporation | Aryloxy-alkyl-dialkylamines |
WO1999025687A1 (en) | 1997-11-14 | 1999-05-27 | G.D. Searle & Co. | Aromatic sulfone hydroxamic acid metalloprotease inhibitor |
US6750228B1 (en) | 1997-11-14 | 2004-06-15 | Pharmacia Corporation | Aromatic sulfone hydroxamic acid metalloprotease inhibitor |
US20010039287A1 (en) * | 1997-11-14 | 2001-11-08 | Thomas E Barta | Aromatic sulfone hydroxamic acid metalloprotease inhibitor |
GB9725782D0 (en) | 1997-12-05 | 1998-02-04 | Pfizer Ltd | Therapeutic agents |
ID25639A (id) * | 1998-02-19 | 2000-10-19 | American Cyanamid Co | Alkil, aril atau heteroarilamida tersubstitusi n-hidroksi-2-(alkil, aril, atau heteroaril sulfanil, sulfinil atau sulfonil)-3 sebagai inhibitor matriks mataloproteinase |
PT1004578E (pt) * | 1998-11-05 | 2004-06-30 | Pfizer Prod Inc | Derivados hidroxamida do acido 5-oxo-pirrolidino-2-carboxilico |
AR035311A1 (es) * | 1999-01-27 | 2004-05-12 | Wyeth Corp | Derivados de acido hidroxamico que contienen alquinilo, como inhibidores de las metalloproteinasas de matriz y de la tace, composicion farmaceutica y el uso de los mismos para la manufactura de un medicamento |
US6753337B2 (en) | 1999-01-27 | 2004-06-22 | Wyeth Holdings Corporation | Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors |
BR0007784A (pt) * | 1999-01-27 | 2002-02-05 | American Cyanamid Co | Composto, método para inibir mudanças patológicas mediadas pela enzima que converte o tnf-alfa (tace) em um mamìfero, composição farmacêutica, e, processo para preparar um composto |
US6946473B2 (en) | 1999-01-27 | 2005-09-20 | Wyeth Holdings Corporation | Preparation and use of acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as TACE inhibitors |
AR035312A1 (es) * | 1999-01-27 | 2004-05-12 | Wyeth Corp | Compuestos de acido hidroxamico que contienen alquinilo como inhibidores de metaloproteinasa de matriz/tace, composicion farmaceutica que los comprenden y el uso de los mismos para la manufactura de un medicamento |
US6340691B1 (en) | 1999-01-27 | 2002-01-22 | American Cyanamid Company | Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and tace inhibitors |
GEP20043238B (en) * | 1999-02-08 | 2004-05-25 | Searle & Co | Sulfamato Hydroxamic Acid Metalloprotease Inhibitor, its Use in Preparation of Pharmaceutical Composition for Treatment of Conditions Associated with Pathological Matrix Metalloprotease Activity |
US6800646B1 (en) | 1999-02-08 | 2004-10-05 | Pharmacia Corporation | Sulfamato hydroxamic acid metalloprotease inhibitor |
SE9901572D0 (sv) | 1999-05-03 | 1999-05-03 | Astra Ab | New compounds |
US6511993B1 (en) | 1999-06-03 | 2003-01-28 | Kevin Neil Dack | Metalloprotease inhibitors |
WO2001055112A1 (en) * | 2000-01-27 | 2001-08-02 | American Cyanamid Company | Method for preparing alpha-sulfonyl hydroxamic acid derivatives |
US6683093B2 (en) | 2000-05-12 | 2004-01-27 | Pharmacia Corporation | Aromatic sulfone hydroxamic acids and their use as protease inhibitors |
PL367487A1 (en) | 2001-05-11 | 2005-02-21 | Pharmacia Corporation | Aromatic sulfone hydroxamates and their use as protease inhibitors |
US6683078B2 (en) | 2001-07-19 | 2004-01-27 | Pharmacia Corporation | Use of sulfonyl aryl or heteroaryl hydroxamic acids and derivatives thereof as aggrecanase inhibitors |
CN100525763C (zh) | 2002-03-05 | 2009-08-12 | 特兰斯泰克制药公司 | 抑制配体与高级糖化终产物受体相互作用的单和双环吡咯衍生物 |
US7119203B2 (en) | 2002-04-25 | 2006-10-10 | Pharmacia Corporation | Piperidinyl- and piperazinyl-sulfonylmethyl hydroxamic acids and their use as protease inhibitors |
EP1515951A1 (en) * | 2002-06-25 | 2005-03-23 | Pharmacia Corporation | Arylsulfonylhydroxamic acid and amide derivatives and their use as protease inhibitors |
US7098241B2 (en) | 2002-12-16 | 2006-08-29 | Hoffmann-La Roche Inc. | Thiophene hydroxamic acid derivatives |
US7423176B2 (en) | 2004-04-13 | 2008-09-09 | Cephalon, Inc. | Bicyclic aromatic sulfinyl derivatives |
WO2007070760A2 (en) | 2005-12-15 | 2007-06-21 | Boehringer Ingelheim International Gmbh | Compounds which modulate the cb2 receptor |
CA2657247A1 (en) | 2006-07-28 | 2008-01-31 | Boehringer Ingelheim International Gmbh | Compounds which modulate the cb2 receptor |
EP2074084B1 (en) | 2006-09-25 | 2013-08-28 | Boehringer Ingelheim International GmbH | Compounds which modulate the cb2 receptor |
MX2009003763A (es) | 2006-10-05 | 2009-04-22 | Janssen Pharmaceutica Nv | Inhibidores de metaloproteasa derivados de heterociclicos. |
US7879911B2 (en) | 2007-02-01 | 2011-02-01 | Johnson Alan T | Hydroxamic acid derivatives of phenoxy-acetic acids and analogs useful as therapeutic agents for treating anthrax poisoning |
WO2009061652A1 (en) | 2007-11-07 | 2009-05-14 | Boehringer Ingelheim International Gmbh | Compounds which modulate the cb2 receptor |
US8178568B2 (en) | 2008-07-10 | 2012-05-15 | Boehringer Ingelheim International Gmbh | Sulfone compounds which modulate the CB2 receptor |
WO2010036630A2 (en) | 2008-09-25 | 2010-04-01 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the cb2 receptor |
US8299103B2 (en) | 2009-06-15 | 2012-10-30 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the CB2 receptor |
WO2010147791A1 (en) | 2009-06-16 | 2010-12-23 | Boehringer Ingelheim International Gmbh | Azetidine 2 -carboxamide derivatives which modulate the cb2 receptor |
US8383651B2 (en) | 2009-09-22 | 2013-02-26 | Boehringer Ingelheim International Gmbh | Compounds which selectively modulate the CB2 receptor |
WO2011041198A1 (en) | 2009-09-30 | 2011-04-07 | Transtech Pharma, Inc. | Substituted imidazole derivatives for treatment of alzheimers disease |
CA2774250C (en) * | 2009-10-13 | 2013-12-17 | Pfizer Inc. | C-linked hydroxamic acid derivatives useful as antibacterial agents |
EP2523936A1 (en) | 2010-01-15 | 2012-11-21 | Boehringer Ingelheim International GmbH | Compounds which modulate the cb2 receptor |
US8329735B2 (en) | 2010-03-05 | 2012-12-11 | Boehringer Ingelheim International Gmbh | Tetrazole compounds which selectively modulate the CB2 receptor |
JP5746764B2 (ja) | 2010-07-22 | 2015-07-08 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Cb2受容体を調節する化合物 |
EP2617812B1 (en) * | 2010-09-17 | 2019-03-20 | The University of Tokyo | Composition for maintaining platelet function |
ES2603740T3 (es) * | 2012-07-18 | 2017-03-01 | Proyecto De Biomedicina Cima, S.L. | Nuevos compuestos antifibrinolíticos |
EP2803668A1 (en) | 2013-05-17 | 2014-11-19 | Boehringer Ingelheim International Gmbh | Novel (cyano-dimethyl-methyl)-isoxazoles and -[1,3,4]thiadiazoles |
EP3143007B1 (en) | 2014-05-16 | 2018-07-11 | Idorsia Pharmaceuticals Ltd | Antibacterial quinazoline-4(3h)-one derivatives |
CN107188837B (zh) * | 2017-06-06 | 2019-05-28 | 温州大学 | 一种α-酰基高烯丙基硫醚类化合物的合成方法 |
US20210393632A1 (en) | 2018-10-04 | 2021-12-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Egfr inhibitors for treating keratodermas |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS50121218A (no) * | 1974-03-01 | 1975-09-23 | ||
DE2424742C3 (de) * | 1974-05-21 | 1982-04-22 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Thiophenderivate Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel |
US3994997A (en) * | 1975-05-09 | 1976-11-30 | Gulf Oil Corporation | O,O-diethyl-O-carboxamidophosphate esters |
GB1520812A (en) * | 1975-10-02 | 1978-08-09 | Lafon Labor | Benzhydrylsulphinyl derivatives |
GB1574822A (en) * | 1976-03-23 | 1980-09-10 | Lafon Labor | Acetohydroxamic acid derivatives and pharmaceutical compositions thereof |
FR2528041A1 (fr) * | 1982-06-04 | 1983-12-09 | Lafon Labor | Acides halogenobenzhydrylsulfinylacetohydroxamiques, procede de preparation et utilisation en therapeutique |
FR2561646B1 (fr) * | 1984-03-23 | 1987-10-09 | Lafon Labor | Derives d'acide (a-(alkylaminomethyl)-benzyl)-thioacetique, procede de preparation et utilisation en therapeutique |
IL92915A0 (en) * | 1989-01-05 | 1990-09-17 | Ciba Geigy Ag | Certain pyrrolylphenyl-substituted hydroxamic acid derivatives |
DE69309047T2 (de) * | 1992-04-07 | 1997-09-11 | British Biotech Pharm | Hydroxamsäure enthaltende collagenase-inhibitoren und cytokinaktivitätsinhibitoren |
US5455258A (en) * | 1993-01-06 | 1995-10-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
FR2708201B1 (fr) * | 1993-06-30 | 1995-10-20 | Lafon Labor | Utilisation de dérivés d'acétamide pour la fabrication de médicaments. |
GB9416897D0 (en) * | 1994-08-20 | 1994-10-12 | British Biotech Pharm | Metalloproteinase inhibitors |
WO1996035714A1 (en) * | 1995-05-10 | 1996-11-14 | Chiroscience Limited | Peptide compounds which inhibit metalloproteinase and tnf liberation and their therapeutic uses |
US5665777A (en) * | 1995-11-14 | 1997-09-09 | Abbott Laboratories | Biphenyl hydroxamate inhibitors of matrix metalloproteinases |
ES2217386T3 (es) * | 1996-01-02 | 2004-11-01 | Aventis Pharmaceuticals Inc. | Compuestos de acido(aril, heteroaril, arilmetil o heteroarilmetil) hidroxamico sustituido. |
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