NO326822B1 - Anvendelse av cyklooksygenase-2 inhibitorer for fremstilling av et medikament for behandling av neoplasi - Google Patents
Anvendelse av cyklooksygenase-2 inhibitorer for fremstilling av et medikament for behandling av neoplasi Download PDFInfo
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- NO326822B1 NO326822B1 NO19991793A NO991793A NO326822B1 NO 326822 B1 NO326822 B1 NO 326822B1 NO 19991793 A NO19991793 A NO 19991793A NO 991793 A NO991793 A NO 991793A NO 326822 B1 NO326822 B1 NO 326822B1
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- Norway
- Prior art keywords
- pyrazol
- cancer
- trifluoromethyl
- difluoromethyl
- compound
- Prior art date
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- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- IQDSXWRQCKDBMW-NSFJATOBSA-N vintriptol Chemical compound C([C@@H](C[C@@](O)(CC)C1)C[C@@]2(C3=C(OC)C=C4N(C)[C@H]5[C@@]([C@@H]([C@]6(CC)C=CCN7CC[C@]5([C@H]67)C4=C3)O)(O)C(=O)N[C@@H](CC=3C4=CC=CC=C4NC=3)C(=O)OCC)C(=O)OC)N1CCC1=C2NC2=CC=CC=C12 IQDSXWRQCKDBMW-NSFJATOBSA-N 0.000 description 1
- 229950003415 vintriptol Drugs 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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Description
Foreliggende oppfinnelse ligger i området for forebygging og behandling av neoplasi. Mer spesifikt angår den foreliggende oppfinnelsen anvendelsen av cyklooksygenase-2 inhibitorer eller derivater derav for fremstilling av et medikament for behandling av neoplasi.
Prostaglandiner spiller en viktig rolle i inflammasjonsprosessen og inhibering av prostaglandinproduksjon, særlig produksjon av PGG2, PGH2 og PGE2, har blitt et alminnelig mål ved oppdagelse av antiinflammasjonslegemidler. Imidlertid er alminnelige ikke-steroidale antiinflammasjonslegemidler (NSAID'er) som er effektive til å redusere den prostaglanclininduserte smerten og svelling tilknyttet inflammasjonsprosessen også effektive til å påvirke andre prostaglandinregulerende prosesser ikke tilknyttet inflammasjonsprosessen. Således kan anvendelsen av høye doser av de mest vanlige NSAED'ene gi alvorlige bivirkninger, inkludert livstruende ulcus, som begrenser deres terapeutiske potensial. Et alternativ til NSAID'er er anvendelsen av kortikosteroider, som også gir alvorlige bivirkninger, særlig ved langtidsbehandling.
NSAID'er er funnet å forebygge produksjonen av prostaglandiner ved inhibering av enzymer i den humane arakidonsyre/prostaglandinbanen, inkluderende enzymet cyklooksygenase (COX). Den nylige oppdagelsen av et induserbart enzym tilknyttet inflammasjon (betegnet "cyklooksygenase-2 (COX-2)" eller "prostaglandin G/H syntase II") tilveiebringer et levedyktig mål for inhibering som reduserer inflammasjon mer effektivt og gir færre og mindre alvorlige bivirkninger.
Forbindelser som selektivt inhiberer cyklooksygenase-2 er beskrevet i US-patentene 5.380.738,5.344.991,5.393.790, 5.434.178,5.474.995, 5.510.368 og WO-dokumentene WO96/06840, WO96/03388, WO96/03387, WO96/25405, W095/15316, W094/15932, WO94/27980, WO95/00501, W094/13635, WO94/20480 ogW094/26731.
Neoplastiske sykdomstilstander er alvorlige og ofte livstruende tilstander. Disse neoplastiske sykdommene, som er kjennetegnet ved rask cellevekst ved proliferasjon, fortsetter å være målet for verdensomspennende forskningsinnsats rettet mot identifiseringen av terapeutiske midler som er effektive i behandlingen derav. Effektive terapeutiske midler forlenger pasientens levetid, inhiberer den raske proliferasjons-celleveksten tilknyttet neoplasien, eller gir en regresjon av neoplasien. Forskning på dette området er primært fokusert mot å identifisere midler som vil være terapeutisk effektive hos mennesker og andre pattedyr.
Nylig har tilstedeværelsen av COX-2 blitt observert i neoplastiske sykdommer. Se Masanobu Oshima et al. (Cell, 87, 803-809 (1996); og Michelle Parret et al.
(International Journal of Oncology, 10,503-507 (1997).
[Pyrazol-l-yl]benzensulfonamider er blitt beskrevet som inhibitorer av cyklooksygenase-2 og har vist seg lovende ved behandling av inflammasjon, artritt og smerte, med minimale bivirkninger i prekliniske og kliniske forsøk. Deres anvendelse ved forebygging av kolonkreft er beskrevet i US patent nr. 5.466.823. Imidlertid har deres anvendelse ved behandling av kolonkreft eller ved behandling eller forebygging av andre neoplasier ikke tidligere blitt beskrevet.
Den foreliggende oppfinnelsen er rettet mot anvendelsen av inhibitorer av cyklooksygenase-2 for fremstilling av et medikament for behandling og forebygging av neoplasier. Konjunktivisk behandling av en selektiv cyklooksygenase-2 inhibitor med andre neoplastiske midler gir en synergistisk effekt eller alternativt reduserer de toksiske bivirkningene tilknyttet kjemoterapi ved reduksjon av konsentrasjonen av det bivirkningsforårsakende midlet som behøves for terapeutisk effektivitet.
Den foreliggende oppfinnelsen kan bidra til en fremgangsmåte for behandling og forebygging av neoplasi som produserer et prostaglandin i et subjekt som trenger slik behandling eller forebygging, hvor fremgangsmåten innbefatter behandling av subjektet med en terapeutisk effektiv mengde av en cyklooksygenase-2 inhibitor eller derivat derav.
Begrepet "behandling" inkluderer delvis eller total inhibering av neoplasi-veksten, spredning eller metastaser, så vel som delvis eller total destruksjon av neoplasi-celler.
Begrepet "forebygging" inkluderer enten forebygging av begynnelsen av klinisk evident neoplasi som sådan eller forebygging av en preklinisk evident tilstand av neoplasi hos individer med risiko. Også ment å bli omfattet av denne definisjonen er forebyggingen av initiering for maligne celler eller å stoppe eller reversere progresjonen av premaligne celler til maligne celler. Dette inkluderer profylaktisk behandling av de med risiko for utvikling av neoplasi.
Uttrykket "terapeutisk effektiv" er ment å omfatte mengden av hvert middel som vil oppnå målsetningen om forbedring i sykdommens alvorlighet og frekvensen av forekomst i forhold til behandling med hvert enkelt middel, samtidig som man unngår alvorlige bivirkninger som typisk er tilknyttet alternative behandlinger.
Begrepet "subjekt" som skal gjøres gjenstand for behandling inkluderer et hvilket som helst humant eller pattedyrsubjekt som har en hvilken som helst av de kjente neoplasier, og foretrukket er et humant subjekt. For fremgangsmåter for forebygging, er subjektet et hvilket som helst humant eller animalsk subjekt, og foretrukket er et humant subjekt som har risiko for å oppnå en epithelium celleavledet neoplasi. Subjektet kan ha risiko på grunn av eksponering for karsinogene midler, være genetisk disponert for å få neoplasi og lignende.
Begrepet "neoplasi" inkluderer neoplasi som gir prostaglandiner eller uttrykker en cyklooksygenase, inkluderende både godartede og kanserogene tumorer, vekster og polypper.
I fremgangsmåten ovenfor inkluderer neoplasien som gir prostaglandiner hjernekreft, benkreft, epitelialcelleavledet neoplasi (epithelial carcinoma) slik som basalcelle carcinoma, adenocarcinoma, gastrointestinalkreft slik som leppekreft, munnkreft, esophogeal kreft, tynntarmkreft og mavekreft, kolonkreft, leverkreft, blærekreft, pankreaskreft, ovariekreft, livmorhalskreft, lungekreft, brystkreft og hudkreft, slik som skjelettcelle- og basalcellekreft, prostatakreft, nyrecelle carcinoma og andre kjente krefttyper som påvirker epitelceller i kroppen. Foretrukket er neoplasi valgt fra gastrointestinalkreft, leverkreft, blærekreft, pankreaskreft, ovariekreft, prostatakreft, livmorhalskreft, lungekreft, brystkreft og hudkreft, slik som skjelettcelle- og basalcellekreft. COX-2 inhibitorene kan også anvendes for å behandle fibrosene som inntreffer ved strålingsbehandling. Fremgangsmåten kan anvendes for behandling av subjekter som har adenomatøse polypper, inkluderende de med familiær adenomatøs polyposis (F AP).
I tillegg kan fremgangsmåten anvendes ved forebygging av dannelsen av polypper hos pasienter med risiko for FAP.
Inhibitorer for cyklooksygenasebanen i metabolismen av arakidonsyre anvendt ved behandling og forebygging av epitelialcelleavledet neoplasier kan inhibere enzymaktivitet ved et antall mekanismer. For eksempel kan inhibitorene anvendt i fremgangsmåtene beskrevet heri blokkere enzymaktiviteten direkte ved å virke som et substrat for enzymet. Anvendelsen av cyklooksygenase-2 selektive inhibitorer er svært fordelaktige ved at de minimaliserer de gastriske bivirkningene som kan finne sted ved ikke-selektive NSAID'er, særlig hvor forlenget profylaktisk behandling er ventet.
Begrepet "cyklooksygenase-2 inhibitor" betegner en forbindelse som er i stand til å inhibere cyklooksygenase-2 uten signifikant inhibering av cyklooksygenase-1. Foretrukket inkluderer det forbindelser som har en cyklooksygenase-2 IC50 på mindre enn ca. 0,2 um, og også har et selektivitetsforhold på cyklooksygenase-2 inhibering i forhold til cyklooksygenase-1 inhibering på minst 50, og mer foretrukket på minst 100. Enda mer foretrukket har forbindelsene en cyklooksygenase-1 IC50 på større enn ca. 1 um, og mer foretrukket på større enn 10 um. Pyrazoler kan fremstilles ved fremgangsmåter beskrevet i W095/15316, W095/15315 og WO96/03385. Tiofen-analoger kan fremstilles ved fremgangsmåter beskrevet i WO95/00501 og W094/15932. Oksazoler kan fremstilles ved fremgangsmåter beskrevet i PCT-dokumentene WO95/00501 og WO94/27980. Isoksazoler kan fremstilles ved fremgangsmåtene beskrevet i WO96/25405. Imidazoler kan fremstilles ved fremgangsmåtene beskrevet i WO96/03388 og WO96/03387. Cyklopenten-cyklooksygenase-2 inhibitorer kan fremstilles ved fremgangsmåtene beskrevet i US patent nr. 5.344.991 og WO95/00501. Terfenylforbindelser kan fremstilles ved fremgangsmåter beskrevet i W096/16934. Tiazolforbindelser kan fremstilles ved fremgangsmåter beskrevet i WO96/03392. Pyridinforbindelser kan fremstilles ved fremgangsmåter beskrevet i W096/24584 og W096/24585.
Foreliggende oppfinnelse omfatter følgelig anvendelse av en forbindelse med formel II
hvori R<4> er metyl substituert med to eller tre fluoratomer; hvori R<5> er hydrido; og hvori R<6> er fenyl substituert i 4-stilling med en substituent valgt fra klor, fluor, metoksy, metyl eller N,N-dimetylamino eller R<6> er 3-fluor-4-metoksyfenyl; eller et farmasøytisk
akseptabelt salt derav, for fremstilling av et medikament for behandling av en neoplasi hos et subjekt.
En familie av spesifikke forbindelser med spesiell interesse innen formel I består av forbindelser og farmasøytisk akseptable salter derav som følger: 4-[5-(4-klorfenyl)-3 -(trilfuormetyl)-1 H-pyrazol-1 -yl]benzensulfonamid; 4-[5-(4-lfuorfenyl)-3 -(trilfuormetyl)-1 H-pyrazol-1 -yl]benzensulfonamid; 4-[5-(4-metoksyfaryl)-3-(trifluorme1yl)4H-pyrazol4-yl]benzensulfonamid; 4-[5-(4-klorfenyl)-3-(d^lfuonnetyl)-lH-pyrazol-l-yl]benzensulfonamid; 4-[5-(4-metylfenyl)-3-(trilfuormetyl)-lH-pyrazol-l-yl]benzensulfonamid; 4-[3-(dilfuormetyl)-5-(4-metylfenyl)-1 H-pyrazol-1 -yljbenzensulfonamid; 4-[3-(dilfuormetyl)-5-(4-metoksyfenyl)-1 H-pyrazol-1 -yljbenzensulfonamid; 4- [3 -(difluormetyl)-5-(3-fluor-4-metoksyfenyl)-1 H-pyrazol-1 -yljbenzensulfonamid;
4-[5-(3-lfuor-4-metoksyfenyl)-3-(trifluometyl)-lH-pyrazol-l-yl]benzensulfonam og 4-[5-(4-(N,N-dimetylamino)fenyl)-3 -(trifluormetyl)-1 H-pyrazol-1 -yljbenzensulfonamid.
En familie av spesifikke forbindelser med mer særlig interesse innen formel II består av forbindelser og farmasøytisk akseptable salter eller derivater derav som følger: 4-[5-(4-metylfenyl)-3-(trilfuorometyl)-lH-pyrazol-l-yl]benzensulfonamid; 4-[5-(4-klorofenyl)-3-(dilfuorometyl)-1 H-pyrazol-1 -yljbenzensulfonamid; og 4-[5-(3-fluoro-4-metoksyfenyl)-3 -(difluorometyl)-1 H-pyrazol-1 -yljbenzensulfonamid. Forbindelsene anvendt ifølge den foreliggende oppfinnelsen kan være til stede i form av frie baser eller farmasøytisk akseptable syreaddisjonssalter derav. Begrepet "farmasøytisk akseptable salter" omfatter salter som vanligvis anvendes for å danne alkalimetallsalter og for å danne syreaddisjonssalter av frie syrer eller frie baser. Beskaffenheten av saltet er ikke kritisk, forutsatt at det er farmasøytisk akseptabelt. Egnede farmasøytisk akseptable syreaddisjonssalter av forbindelser med formel I kan fremstilles fra en uorganisk syre eller fra en organisk syre. Eksempler på slike uorganiske syrer er saltsyre, hydrobromsyre, hydrojodsyre, salpetersyre, karbonsyre, svovelsyre og fosforsyre. Hensiktsmessige organiske syrer kan velges ut fra alifatiske, cykloalifatiske, aromatiske, aralifatiske, heterocykliske, karboksyliske og sulfonklasser av organiske syrer, eksempler på dette er maursyre, eddiksyre, propionsyre, ravsyre, glykolsyre, glukonsyre, melkesyre, eplesyre, vinsyre, sitronsyre, askorbinsyre, glukuronsyre, maleinsyre, fumarsyre, pyrodruesyre, asparaginsyre, glutaminsyre, benzosyre, antranilsyre, mesylsyre, 4-hydroksybenzosyre, fenyleddiksyre, mandelsyre, embonsyre (pamosyre), metansulfonsyre, etansulfonsyre, benzensulfonsyre, pantotensyre, 2-hydroksyetansulfonsyre, toluensulfonsyre, sulfanilsyre, cykloheksylaminosulfonsyre, stearinsyre, algensyre, B-hydroksysmørsyre, salicylsyre, galaktarsyre og galakturonsyre. Hensiktsmessige farmasøytisk akseptable baseaddisjonssalter av forbindelser med formel I inkluderer metallsalter fremstilt fra aluminium, kalsium, litium, magnesium, kalium, natrium og sink eller organiske salter fremstilt fra kloroprokain, cholin, N,N'-dibenzyletylendiamin, dietanolamin, etylendiamin, meglumin (N-metylglukamin) og prokain. Alle disse salter kan fremstilles ved vanlige fremgangsmåter fra den korresponderende forbindelsen til formel I ved å reagere, for eksempel, den hensiktsmessige syren eller basen med forbindelsen med formel I.
Effektiviteten av cyklooksygenase-2 inhibitorer som antineoplasia-midler ble bestemt i de følgende modeller:
Murin Lewis lungekarcinom modell
Lewis lungekarcinomer ble implantert subkutant i fotsålen på C57BL/6 hannmus. Musene ble deretter behandlet med 4-[5-(4-klorofenyl)-3-(dilfuorometyl)-lH-pyrazol-l-yljbenzensulfonamid. Legemidlet ble tilført i drikkevannet med 6 mg/kg/dag. Det ble også testet en ikke-selektiv COX-1 /COX-2 inhibitor indomethacin i denne modellen. Legemidlet ble tilført i drikkevannet ved maksimal tolererende dose på 2 mg/kg/dag. Totalt ble 10 mus/forbindelse testet. Tumorvolum ble bestemt to ganger per uke ved anvendelse av et plethysmometer. Effektiviteten av disse forbindelsene på tumorvekst ble målt ved dag 32 etter kreftcelleinjeksjon, som indikert i Tabell 1. Prosentinhiberingsverdien ble beregnet ved å bestemme forskjellen i tumorstørrelse sammenlignet med kontrollgruppen.
Human prostatakreftcelletumorer
To humane prostatakretfcellelinjer (PC-3 og LNCaP) ble oppnådd (ATCC) for å bestemme effektiviteten av cyklooksygenase-2 inhibitorer til å inhibere tumorvekst i en terapeutisk modell. I tillegg skiller LNCaP cellelinjen ut prostataserum antigen (PSA) ved dyrkning på nakne mus.
PC-3
PC-3 celler (IO<6> celler/0,2 ml av 30% matrigel) i RPMI1640 medium ble injisert i ryggen på nakne mus. Ved dag 28 ble en COX-2 inhibitor 4-[5-(4-klorofenyl)-3-(difluorometyl)-lH-pyrazol-l-yl]benzensulfonamid (20 mg/kg/dag i vann) administrert. Etter 45 dager ble PGE2 og TXB2 målt. COX-2 inhibitoren inhiberte tumorvekst med 55%. PGE2- og TXB2-nivåene ble redusert med 80-90% hos dyr behandlet med COX-2 inhibitoren.
LNCaP
Tilsvarende resultatene i PC-3 inhiberte en COX-2 inhibitor 4-[5-(4-klorofenyl)-3-(difluorometyl)-l H-pyrazol-l-yl]benzensulfonamid i en dose ekvivalent med 6 mg/kg/dag i drikkevannet veksten av tumoren med 55% ved dag 58. PSA-nivå ble redusert til ca. 50% målt med "western blotting".
Annet
Cellelinjer: Følgende cellelinjer kan anvendes: Klassiske småcellelungekreft (SCLC) cellelinjer NCI-H209, NCI-H345 og NCI-H510; variant SCLC cellelinjer NCI-N417 og NCI-H82; storcelle-carcinoma cellelinje NCI-H1155; adenocarcinoma-cellelinje NCI-H23; og bronkioalveolær carcinoma cellelinje A549, brystkreft cellelinje MCF-7 (American Type Tissue Culture Rockville MD; ATCC) og kolonkreft cellelinjer slike som NCI-H630 (ATCC), HT 29, SW948, HCA-7 og andre som kan testes in vivo eller in vitro. Alle celler kan dyrkes i RPMI-1640, supplert med fosterkvegserum (FBS), penicillin og streptomycin (Gibco, Grand Island, NY), og ble holdt i en 5% CO2-atmosfære ved 37°C. Alle cellelinjene er uten mycoplasmaforurensning.
Vekststudier: En modifikasjon (Promega CellTiter 96®, Promega Madison, WI) av den halvautomatiserte kolorimetriske undersøkelsen, MTT [Nakanishi et al., Exper. Cell
Biol., 56,74-85 (1988)], som kvantifiserer celleantallet basert på reduksjon av en tetrazolium-forbindelse av tumorceller som bestemt ved et spektrofotometer (540 nm) ble anvendt. Alle undersøkelser ble utført i RPMI-1640 media supplert med transfertin -10 g/ml, insulin ~5 g/ml og selen (Sigma Chemicals, St. Louis, MO). Såingstetthetene er ~ 2xl0<4> celler/brønn, og celler ble dyrket i 5 dager. Hvert eksperiment ble rapportert som gjennomsnittlig optisk tetthet korrigert for bakgrunn +/- standardavvik. Cyklooksygenase-2 inhibitorene bør være aktive, ved en dose på 20 mg/kg, til å inhibere vekst av kreftcellelinjene.
En museurinblære-tumormodell ble utført med materialer, reagenser og fremgangsmåter essensielt som beskrevet av Grabbs et al. [ Anticancer Res., 13,33-36 (1993)]. En COX-2 inhibitor bør være aktiv ved en dose på 20 mg/kg.
En rottebryst-tumormodell ble utført med materialer, reagenser og fremgangsmåter essensielt som beskrevet av Grabbs et al. [ Anticancer Res., 15,709-16 (1995)]. En COX-2 inhibitor bør være aktiv ved en dose på 20 mg/kg.
En muse livmorhals- og vaginalcarcinogenese-modell ble utført med materialer, reagenser og fremgangsmåter essensielt som beskrevet av Arbeit et al. [ Proe. Acad. Sei. USA, 93,2930-35 (1996)]. En COX-2 inhibitor bør være aktiv ved en dose på 20 mg/kg.
En colonadenocarcinoma-cellemodell ble utført med materialer, reagenser og fremgangsmåter essensielt som beskrevet av Shiff et al. [ J. Clin. Invest., 96,491-503
(1995)]. En COX-2 inhibitor bør være aktiv ved en dose på 20 mg/kg. Se også Masahiko Tsujii et al. (Proe. Nati. Acad. Sei. USA 94: 3336-3340, 1997).
I sum reduserer COX-2 inhibitorer tumorvekst hos flere dyrekreftmodeller.
Kombinasjonsterapi av en COX-2 inhibitor og andre antineoplastiske midler
Lewis lungecarcinoma celler (2,5 x IO<6> celler) fremstilt fra en væske båret i C57BL/6 mus ble injisert subkutant til bakbenet av mus. En COX-2 inhibitor, 4-[5-(4-klorofenyl)-3-(difluorometyl)-l H-pyrazol-l-yl]benzensulfonamid, ble gitt ved magesonde to ganger per uke til grupper på 10 mus ved doser på 6 og 20 mg/kg. Cyklofosfamid (CTX) ble injisert til mus på dagene 5,7 og 9 etter implanteringen av tumoren ved en dose på 50 mg/kg. Tumorvolumet ble bestemt i løpet av studien. Dyr ble anlivet ved dag 26 og resultatene av disse eksperimentene er summert i Tabell 2. Prosent inhibering ble beregnet som ovenfor.
Resultatene av disse eksperimentene viser at kombinasjonen av en COX-2 inhibitor og et cytotoksisk middel gir en additiv effekt på deres individuelle kapasitet til å inhibere tumorvekst.
De aktive forbindelsene anvendt ifølge oppfinnelsen kan administreres på en hvilken som helst hensiktsmessig måte kjent for fagfolk, foretrukket i form av en farmasøytisk akseptabel sammensetning egnet for en slik fremgangsmåte, og i en dose som er effektiv for den tiltenkte behandlingen. De aktive forbindelsene og sammensetningene kan for eksempel bli administrert oralt, intravaskulært, intraperitonealt, intranasalt, intrabronkialt, subkutant, intramuskulært eller topisk (inkluderende aerosol).
Hensikten med administrasjonen kan være enten forebygging eller behandling. Fremgangsmåtene og medikamentene kan anvendes alene eller i forbindelse med ytterligere behandlinger kjent for fagfolk ved forebygging eller behandling av neoplasi. Alternativt kan fremgangsmåter og medikamenter anvendes som konjunktivisk behandling. For eksempel kan cyklooksygenase-2 inhibitoren som anvendes ifølge oppfinnelsen bli administrert alene eller i forbindelse med andre antineoplastiske midler eller andre vekstinhiberende midler eller andre legemidler eller næringsstoffer.
Det er et stort antall av antineoplastiske midler tilgjengelig for kommersiell anvendelse, ved klinisk evaluering og ved preklinisk utvikling, som kan velges ut ved behandling av neoplasi ved kombinasjonslegemiddel-kjemoterapi. Slike antineoplastiske midler faller i flere hovedkategorier, nemlig antibiotisk type midler, alkyleringsmidler, antimetabolittmidler, hormonmidler, immunologiske midler, interferon type midler og en kategori med diverse midler. Alternativt kan antineoplastiske midler, slike som metallomatriksproteaser (MMP), SOD mimetiske midler eller avfl3 inhibitorer, bli anvendt.
En første familie av antineoplastiske midler som kan anvendes i kombinasjon med en selektiv cyklooksygenase-2 inhibitor består av antimetabolitt-type antineoplastiske midler. Hensiktmessige antimetabolitt-antineoplastiske midler kan velges ut fra en gruppe bestående av 5-FU-fibrinogen, acanthifolsyre, aminotiadiazol, brequinar natrium, carmofur, Ciba-Geigy CGP-30694, cyklopentylcytosin, cytarabinfosfatstearat, cytarabinkonjugater, Lilly DATHF, Merrel Dow DDFC, dezaguanin, mdeoksycytidin, dideoksyguanosin, didoks, Yoshitomi DMDC, doksifluridin, Wellcome EHNA, Merck & Co. EX-015, fazarabin, floksuridin, fludarabinfosfat, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizin, Lilly LY-188011, Lilly LY-264618, metobenzaprim, metotreksat, Wellcome MZPES, norspermidin, NCINSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritreksim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, tioguanin, tiazofurin, Erbamont TIF, trimetreksat, tyrosinkinaseinhibitorer, tyrosinproteinkinaseinhibitorer, Taiho UFT og uricytin.
En annen familie av antineoplastiske midler som kan anvendes i kombinasjon med en selektiv cyklooksygenase-2 inhibitor består av alkyleringstype antineoplastiske midler. Egnede alkyleringstype antineoplastiske midler kan utvelges fra en gruppe bestående av Shionogi 254-S, aldo-fosfamidanaloger, altretamin, anaksiron, Boehringer Mannheim BBR-2207, bestrabucil, budotitan, Wakunaga CA-102, karboplatin, karmustin, Chinoin-139, Chinoin-153, klorambucil, cisplatin, cyklofosfamid, American Cyanamid CL-286558, Sanofi CY-233, cyplatat, Degussa D-19-384, Sumimoto DACHP(Myr)2, difenylspiromustin, diplatinum cytostatisk, Erba distamycinderivater, Chugai DWA-2114R, rri E09, elmustin, Erbamont FCE-24517, estramustinfosfatnatrium, fotemustin, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamid, iproplatin, lomustin, mafosfamid, mitolaktol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oksaliplatin, Upjohn PCNU, prednimustin, Prater PTT-119, ranimustin, semustin, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromustin, Tanabe Seiyaku TA-077, tauromustin, temozolomid, teroksiron, tetraplatin og trimelamol.
En tredje familie av antineoplastiske midler som kan anvendes i kombinasjon med en selektiv cyklooksygenase-2 inhibitor består av antibiotisk-type antineoplastiske midler. Egnede antibiotisk-type antineoplastiske midler kan velges ut fra en gruppe bestående av Taiho 4181-A, aclarubicin, actinomycin D, actinoplanon, Erbamont ADR-4S6, aeroplysininderivat, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomyciner, antracyklin, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycinsulfat, bryostatin-1, Taiho C-1027, calichemycin, kromoksimycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doksorubicin, doksorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudiner, kazusamycin, kesarirhodiner, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoksantron, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oksalysin, oksaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin, rhizoksin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangjcin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazin, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 og zorubicin.
En fjerde familie av antineoplastiske midler som kan anvendes i kombinasjon med den selektive cyklooksygenase-2 inhibitoren består av en diversefamilie av antineoplastiske midler utvalgt fra gruppen bestående av alfa-karoten, alfa-difluorometyl-arginin, acitretin, Biotec AD-5, Kyorin AHC-52, alstonin, amonafid, amfethinil, amsacrin, Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, afidicolinglycinat, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantren, Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamid, Wellcome BW-502, Wellcome BW-773, caracemid, carmethizolhydroklorid, Ajinomoto CDAF, klorsulfaquinoksalon, Chemes CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenon, ICN forbindelse 1259, ICN forbindelse 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabin, cytocytin, Merz D-609, DABIS maleat, dakarbazin, datelliptinium, didemnin-B, dihematoporfyrineter, dihydrolenperon, dinalin, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptiniumacetat, Tsumura EPMTC, ergotaimin, etoposid, etretinat, fenretinid, Fujisawa FR-57704, galliumnitrat, genkwaclaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N, heksadecylfosfocholin, Green Cross HO-221, homoharringtonin, hydroksyurea, BTG ICRF-187, ilmofosin, isoglutamin, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamin, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbaron, merocyaninderivater, metylanilinoakridin, Molecular Genenes MGI-136, minactivin, mitonafid, mitoquidon, mopidamol, motretinid, Zenyaku Kogyo MST-16, N-(retmoyl)aminosyrer, Nisshin Flour Milling N-021, N-acylerte-dehydroalaniner, nafazatrom, Taisho NCU-190, nocodazolderivat, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotid, Ono ONO-112, oquizanocin, Akzo Org-10172, pankratistatin, pazelliptin, Warner-Lambert PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptid D, piroksantron, polyhematoporphyrin, polypresyre, Efamol porfyrin, probiman, prokarbazin, proglumid, Invitron protease neksin I, Tobishi RA-700, razoksan, Sapporo Breweries RBS, restriktin-P, retelliptin, retinosyre, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyklopropanderivater, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinon, Stypoldion, Suntory SUN 0237, Suntory SUN 2071, superoksiddismutase, Toyama T-506, Toyama T-680, taksol, Teijin TEI-0303, teniposid, thaliblastin, Eastman Kodak TJB-29, tokotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastinsulfat, vinkristin, vindesin, vinestramid, vinorelbin, vintriptol, vinzolidin, withanolider og Yamanouchi YM-534.
Eksempler på radiobeskyttende midler som kan anvendes i kombinasjonskjemoterapi er AD-5, adchnon, amifostinanaloger, detoks, dimesna, 1-102, MM-159, N-acylerte-dehydroalaniner, TGF- Genentech, tiprotimod, amifostin, WR-151327, FUT-187, ketoprofen transdermal, nabumeton, superoksiddismutase (Chiron) og superoksiddismutase Enzon.
Fremgangsmåter for fremstilling av de antineoplastiske midler beskrevet ovenfor kan finnes i litteraturen. Fremgangsmåter for fremstilling av doksorubicin er for eksempel beskrevet i US-patenter nr. 3.590.028 og 4.012.448. Fremgangsmåter for fremstilling av metallomatriksprotease inhibitorer er beskrevet i EP 780386. Fremgangsmåter for fremstilling av SOD mimetiske midler er beskrevet i EP 524.101. Fremgangsmåter for fremstilling av avB3 inhibitorer er beskrevet i WO97/08174.
Uttrykket "konjunktivisk terapi" (eller "kombinasjonsterapi"), for å definere anvendelsen av et cyklooksygenase-2 inhibitor middel og et annet farmasøytisk middel, kan omfatte administrering av et middel på en sekvensiell måte i et regime som vil tilveiebringe fordelaktige effekter av legemiddelkombinasjonen, og kan også omfatte ko-administrering av disse midlene på en i det vesentlige simultan måte, slik som i en enkel formulering som har en fiksert andel av disse aktive midlene, eller i en multippel, separat formulering for hvert middel.
For oral administrasjon kan det oppnådde medikamentet være i form av for eksempel en
tablett, kapsel, suspensjon eller væske. Medikamentet er foretrukket fremstilt i form av en doseringsenhet som inneholder en bestemt mengde av den aktive ingrediensen. Eksempler på slike doseringsenheter er kapsler, tabletter, pulvere, granuler eller en suspensjon, med vanlige additiver slike som laktose, mannitol, maisstivelse eller potetstivelse; med bindemidler slike som krystallinsk cellulose, cellulosederivater, akasia, maisstivelse eller gelatiner; med desintegratorer slike som maisstivelse, potetstivelse eller natriumkarboksymetyl-cellulose; og med smøremidler slike som talkum eller magnesiumstearat. Medikamentet kan også administreres ved injeksjon som en sammensetning hvori for eksempel saltvann, dekstrose eller vann kan anvendes som en egnet bærer.
For intravenøs, intramuskulær, subkutan eller intraperitoneal administrasjon kan forbindelsen som anvendes kombineres med en steril vandig løsning som foretrukket er isoton med blodet til mottakeren. Slike formuleringer kan fremstilles ved å løse opp faste aktive ingredienser i vann som inneholder fysiologisk kompatible substanser slike som natriumklorid, glycin og lignende, og som har en bufret pH kompatibel med fysiologiske betingelser for å gi en vandig løsning, og som gjør nevnte løsning steril. Formuleringene kan være til stede i enhets- eller flerdosebeholdere slike som forseglede ampuller eller medisinglass.
Hvis neoplasien er lokalisert i tarmkanalen, kan forbindelsen som anvendes formuleres med syrestabile, baselabile bestrykninger kjent i litteraturen som begynner å løse opp i tynntarmen hvor det er høy pH. Formuleringer som øker lokale farmakologiske effekter og reduserer systemisk opptak er foretrukket.
Formuleringer egnede for par enter al administrasjon innbefatter vanligvis et sterilt vandig preparat av den aktive forbindelsen som er foretrukket gjort isotonisk. Preparater for injeksjoner kan også formuleres ved å suspendere eller emulgere forbindelsene i ikke-vandig løsemiddel, slik som vegetabilsk olje, syntetiske alifatiske syreglycerider, estere av høyere alifatiske syrer eller propylenglykol.
Formuleringer for topisk anvendelse inkluderer kjente geler, kremer, oljer og lignende. For aerosoltilføring kan forbindelsene formuleres med kjente aerosol-eksipienter, slike som saltvann, og administreres ved anvendelse av kommersielt tilgjengelige forstøvere. Formulering i en fettsyrekilde kan anvendes for å øke biokompatibiliteten. Aerosol-avlevering er en fordelaktig fremgangsmåte for avlevering ved epithel-neoplasier i lungen ved forebyggende anvendelse.
For rektal administrasjon kan den aktive ingrediensen som anvendes formuleres i stikkpiller ved anvendelse av baser som er faste ved romtemperatur og smelter eller løses opp ved kroppstemperatur. Vanlig anvendte baser inkluderer kakaosmør, glycerinert gelatin, hydrogenert vegetabilsk olje, polyetylenglykoler av varierende molekylvekt og fettestere av polyetylenstearat.
Doseringsformen og mengden kan med enkelhet bli bestemt med referanse til kjent neoplasi-behandling eller profylaktiske regimenter. Mengden av terapeutisk aktiv forbindelse som administreres og doseringsregimet for behandling av en sykdomstilstand med forbindelsene som anvendes ifølge oppfinnelsen avhenger av et antall faktorer, inkluderende alder, vekt, kjønn og medisinsk tilstand av subjektet, alvorligheten av sykdommen, administrasjonsmåte og -frekvens og den spesielle forbindelsen som anvendes, lokaliseringen av neoplasiaen, så vel som de farmakokinetiske egenskapene til individet som behandles, og kan således variere sterkt. Doseringen vil generelt være lavere hvis forbindelsene blir administrert lokalt i forhold til systemisk, og for forebygging er de lavere enn for behandling. Slike behandlinger kan administreres så hyppig som nødvendig og over den tidsperiode som anses nødvendig av den behandlende lege. Fagfolk vil finne det doseringsregimet eller den terapeutisk effektive mengde av inhibitoren som er nødvendig å administrere for å fa et optimalt resultat på hvert individ. Den farmasøytiske sammensetningen kan inneholde aktiv ingrediens i området fra ca. 0,1 til 2000 mg, foretrukket i området fra ca. 0,5 til 500 mg og mest foretrukket mellom ca. 1 og 200 mg. En daglig dose på ca. 0,01 til 100 mg/kg kroppsvekt, foretrukket mellom ca. 0,1 og ca. SO mg/kg kroppsvekt, kan være hensiktsmessig. Den daglige dosen kan administreres i en eller fire doser per dag.
Claims (13)
1.
Anvendelse av en forbindelse med formel II
hvori R<4> er metyl substituert med to eller tre fluoratomer; hvori R<5> er hydrido; og hvori R<6> er fenyl substituert i 4-stilling med en substituent valgt fra klor, fluor, metoksy, metyl eller N,N-dimetylamino eller R<6> er 3-fluor-4-metoksyfenyl; eller et farmasøytisk akseptabelt salt derav, for fremstilling av et medikament for behandling av en neoplasi hos et subjekt.
2.
Anvendelse ifølge krav 1, hvori forbindelsen er utvalgt fra forbindelser, og deres farmasøytisk akseptable salter, fra gruppen bestående av 4-[5-(4-klorfenyl)-3-(trifluormetyl)-1 H-pyrazol-1 -yl]benzensulfonamid; 4-[5-(4-lfuorfenyl)-3 -(trifluormetyl)-1 H-pyrazol-1 -yl]benzensulfonamid; 4-[5-(4-metoksyfenyl)-3-(tirfluormetyl)-1 H-pyrazol-1 -yl]benzensulfonamid; 4-[5-(4-klorfenyl)-3-(difluormetyl)-1 H-pyrazol-1 -yl]benzensulfonamid; 4-[5-(4-me1ylfenyl)-3-(trifluormetyl)-lH-pyrazol-l-yl]benzensulfonamid; 4-[3-(difluormetyl)-5-(4-metylfenyl)-1 H-pyrazol-1 -yljbenzensulfonamid;
4-[3 -(difluormetyl)-5-(4-metoksyfenyl)-1 H-pyrazol-1 -yl]benzensulfonamid; 4-[3-(difluormetyl)-5-(3-fluor-4-metoksyfenyl)-lH-pyrazol-l-yl]benzensulfonan^ 4-[5-(3-fluor-4-metoksyfenyl)-3-(trifluom og 4-[5-(4-(N,N-dimetylammo)fenyl)-3-(ta
3.
Anvendelse ifølge krav 2, hvori forbindelsen er 4-[5-(4-metylfenyl)-3-(trifluormetyl)-1 H-pyrazol-1-yljbenzensulfonamid, eller et farmasøytisk akseptabelt salt derav.
4.
Anvendelse ifølge krav 2, hvori forbindelsen er 4-[5-(4-klorfenyl)-3-(difluormetyl)-lH-pyrazol-l-yl]benzensulfonamid, eller et farmasøytisk akseptabelt salt derav.
5.
Anvendelse ifølge krav 2, hvori forbindelsen er 4-[5-(3-fluor-4-metoksyfenyl)-3 - (difluormetyl)-l H-pyrazol- l-yl]benzensulfonamid, eller et farmasøytisk akseptabelt salt derav.
6.
Anvendelse ifølge krav 1, hvori neoplasien er utvalgt fra colorektal kreft, gastrointestinal kreft, leverkreft, blærekreft, livmorhalskreft, prostatakreft, lungekreft, brystkreft og hudkreft.
7.
Anvendelse av en forbindelse ifølge krav 1 for fremstilling av et medikament for forebygging av en neoplasi utvalgt fra adenomatøse polypper, gastrointestinal kreft, leverkreft, blærekreft, livmorhalskreft, prostatakreft, lungekreft, brystkreft og hudkreft, hos et subjekt som trenger slik forebygging.
8.
Anvendelse ifølge krav 7, hvori forbindelsen er utvalgt fra forbindelser, og deres farmasøytisk akseptable salter, fra gruppen bestående av 4-[5-(4-klorfenyl)-3 -(trifluormetyl)-1 H-pyrazol-1 -yljbenzensulfonamid; 4-[5-(4-lfuorfenyl)-3-(tirfluormetyl)-lH-pyrazol-l-yl]benzensulfonam^ 4- [ 5-(4-metoksyfenyl)-3 -(tirfluormetyl)-1 H-pyrazol-1 -yljbenzensulfonamid; 4-[5-(4-klorfenyl)-3 -(difluormetyl)-1 H-pyrazol-1 -yljbenzensulfonamid; 4-[5-(4-metylfenyl)-3-(trifluormetyl)-1 H-pyrazol-1-yljbenzensulfonamid; 4-[3-(m^uoime1yl)-5-(4-me1ylfenyl)-lH-pyrazol-l-yl]benzensulfonamid; 4-[3-(dilfuormetyl)-5-(4-metoksyfenyl)-lH-pyrazol-l-yl]benzensulfonamM 4-[3-(difluormetyl)-5-(3-fluor-4-metoksyfenyl)-1 H-pyrazol-1 -yljbenzensulfonamid; 4-[5-(3-fluor-4-metolcsyfenyl)-3-(trifluormetyl)-lH-pyrazol-l-yl]benzensulfonam og 4-[5-(4-(N,N-dimetylamino)fenyl)-3-(trifluormetyl)-1 H-pyrazol-1 -yljbenzensulfonamid.
9.
Anvendelse ifølge krav 8, hvori forbindelsen er 4-[5-(4-metylfenyl)-3-(trifluormetyl)-1 H-pyrazol-1-yljbenzensulfonamid, eller et farmasøytisk akseptabelt salt derav.
10.
Anvendelse ifølge krav 8, hvori forbindelsen er 4-[5-(4-klorfenyl)-3-(difluoimetyl)-lH-pyrazol-1 -yljbenzensulfonamid, eller et farmasøytisk akseptabelt salt derav.
11.
Anvendelse ifølge krav 8, hvori forbindelsen er 4-[5-(3-fluor-4-metoksyfenyl)-3-(difluormetyl)-l H-pyrazol-1 -yljbenzensulfonamid, eller et farmasøytisk akseptabelt salt derav.
12.
Anvendelse ifølge krav 1, hvori neoplasien er adenomatøse polypper.
13.
Anvendelse ifølge krav 7, hvori neoplasien er adenomatøse polypper.
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US2849496P | 1996-10-15 | 1996-10-15 | |
PCT/US1997/018670 WO1998016227A1 (en) | 1996-10-15 | 1997-10-14 | Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia |
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1999
- 1999-04-15 NO NO19991793A patent/NO326822B1/no not_active IP Right Cessation
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2000
- 2000-08-04 HK HK00104885A patent/HK1025518A1/xx not_active IP Right Cessation
-
2001
- 2001-02-07 NZ NZ509755A patent/NZ509755A/xx not_active IP Right Cessation
-
2004
- 2004-12-16 IL IL16581604A patent/IL165816A0/xx unknown
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