DK2358697T3 - Isoindolinforbindelser til anvendelse ved behandling af cancer - Google Patents

Isoindolinforbindelser til anvendelse ved behandling af cancer Download PDF

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DK2358697T3
DK2358697T3 DK09741174.8T DK09741174T DK2358697T3 DK 2358697 T3 DK2358697 T3 DK 2358697T3 DK 09741174 T DK09741174 T DK 09741174T DK 2358697 T3 DK2358697 T3 DK 2358697T3
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hydrochloride
methyl
acid
alkyl
inhibitors
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DK09741174.8T
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Alexander L Ruchelman
George W Muller
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Celgene Corp
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Claims (15)

1. Forbindelse med formel I:
eller et farmaceutisk acceptabelt salt, solvat eller stereoisomer deraf, hvor: X er C(=0) eller CH2; Y er O; m er et helt tal på 0,1,2 eller 3; R1 er hydrogen; R2 er -N02, C0-6 alkyl-(5- til 10-leddet heteroaryl), C0-6 alkyl-(5- til 6-leddet heterocyclyl), C0-6 alkyl-OH, C0-4 alkyl-NH2, -NHCO-Ci-6 alkyl, -OR21 eller -(CH2-Z)o-2-(5- til 10-leddet heteroaryl), hvor hvert heteroaryl og heterocyclyl eventuelt er substitueret med et eller flere Ci_6 alkyl; R3 er hydrogen, halogen, -N02, C0-6 alkyl-(5- til 10-leddet heteroaryl), C0-e alkyl-(5- til 6-leddet heterocyclyl), C0-e alkyl-OH, C0-4 alkyl-NH2, -NHCO-Ci-6 alkyl, -OR21 eller -(CH2-Z)0-2-(5- til 10-leddet heteroaryl), hvor hvert heteroaryl og heterocyclyl eventuelt er substitueret med et eller flere Ci_6 alkyl; R21 er C6-io aryl, 5- til 10-leddet heteroaryl, 5- til 6-leddet heterocyclyl, eller -CO(CH2)o-2R22, hvor arylet, heteroarylet og heterocyclylet hver især eventuelt er substitueret med et eller flere Ci_6 alkyl; R22 er -NH2 eller 5- til 6-leddet heterocyclyl; og Z er CH2, NH eller O; forudsat at når R3 er halogen, så er R2 C0-e alkyl-(5-6 leddet heterocyclyl).
2. Forbindelse ifølge krav 1, hvor R2 er amino, acetamido, hydroxy, nitro, aminomethyl, hydroxymethyl, 2-methyl-1 /-/-imidazol-1 -yl, 3-methyl-1,2,4-oxadiazol-5-yl, 4-methylpiperazin-1-yl)methyl, 2-methyl-2/-/-pyrazol-3-yl, 1-methyl-1 /-/-pyrazol-3-yl, 2-methylthiazol-4-yl, 4-methyl-4H-1,2,4-triazol-3-yl, morpholinomethyl, (pyridin-4-yl)methyl, (pyridin-4-yloxy)methyl, phenoxy, py-ridin-2-yloxy, piperidin-4-yloxy, 2-aminoacetoxy eller 2-piperazin-1-ylacetoxy.
3. Forbindelse ifølge krav 1 eller 2, hvor R3 er hydrogen, amino, acetamido, hydroxy, nitro, aminomethyl, hydroxymethyl, 2-methyl-1 H-imidazol-1-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 4-methylpiperazin-1-yl)methyl, 2-methyl-2H-pyrazol-3-yl, 1-methyl-1/-/-pyrazol-3-yl, 2-methylthiazol-4-yl, 4-methyl-4H-1,2,4-triazol-3-yl, morpholinomethyl, (pyridin-4-yl)methyl, (pyridin-4-yloxy)methyl, phenoxy, pyridin-2-yloxy, piperidin-4-yloxy, 2-aminoacetoxy eller 2-piperazin-1-ylacetoxy.
4. Forbindelse ifølge krav 1, som er:
eller et farmaceutisk acceptabelt salt, solvat eller stereoisomer deraf.
5. Forbindelse, som er:
> eller et farmaceutisk acceptabelt salt, solvat eller stereoisomer deraf.
6. Farmaceutisk sammensætning omfattende forbindelsen ifølge et af kravene 1 til 5 og et eller flere farmaceutisk acceptable hjælpestoffer eller bæremidler.
7. Farmaceutisk sammensætning ifølge krav 6, endvidere omfattende et andet terapeutisk middel.
8. Farmaceutisk sammensætning ifølge krav 7, hvor det andet terapeutiske middel er udvalgt fra gruppen bestående af semaxanib; cyclosporin; etaner-cept; doxycyclin; bortezomib; acivicin; aclarubicin; acodazolhydrochlorid; acronin; adozelesin; aldesleukin; altretamin; ambomycin; ametantronacetat; amsacrin; anastrozol; anthramycin; asparaginase; asperlin; azacitidin; azete-pa; azotomycin; batimastat; benzodepa; bicalutamid; bisantrenhydrochlorid; bisnafiddimesylat; bizelesin; bleomycinsulfat; brequinarnatrium; bropirimin; busulfan; cactinomycin; calusteron; caracemid; carbetimer; carboplatin; car-mustin; carubicinhydrochlorid; carzelesin; cedefingol; celecoxib; chlorambucil; cirolemycin; cisplatin; cladribin; crisnatolmesylat; cyclophosphamid; cytarabin; dacarbazin; dactinomycin; daunorubicinhydrochlorid; decitabin; dexormaplatin; dezaguanin; dezaguaninmesylat; diaziquon; docetaxel; doxorubicin; doxorubicinhydrochlorid; droloxifen; droloxifencitrat; dromostano-lonpropionat; duazomycin; edatrexat; eflomithinhydrochlorid; elsamitrucin; enloplatin; enpromat; epipropidin; epirubicinhydrochlorid; erbulozol; esorubi-cinhydrochlorid; estramustin; estramustinphosphatnatrium; etanidazol; etoposid; etoposidphosphat; etoprin; fadrozolhydrochlorid; fazarabin; fenreti-nid; floxuridin; fludarabinphosphat; fluoruracil; flurocitabin; fosquidon; fostrie-cinnatrium; gemcitabin; gemcitabinhydrochlorid; hydroxyurea; idarubicin hy-drochlorid; ifosfamid; ilmofosin; iproplatin; irinotecan; irinotecanhydrochlorid; lanreotidacetat; letrozol; leuprolidacetat; liarozolhydrochlorid; lometrexolnatrium; lomustin; losoxantronhydrochlorid; masoprocol; maytansin; mechlo-rethaminhydrochlorid; megestrolacetat; melengestrolacetat; melphalan; me-nogaril; mercaptopurin; methotrexat; methotrexatnatrium; metoprin; meturedepa; mitindomid; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotan; mitoxantronhydrochlorid; mycophenolsyre; noco-dazol; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustin; peplomycinsulfat; perfosfamid; pipobroman; piposulfan; piroxantronhydrochlorid; plicamycin; plomestan; porfimernatrium; porfiromy-cin; prednimustin; procarbazinhydrochlorid; puromycin; puromycinhydrochlo-rid; pyrazofurin; riboprin; safingol; safingolhydrochlorid; semustin; simtrazen; sparfosatnatrium; sparsomycin; spirogermaniumhydrochlorid; spiromustin; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalannatrium taxoter; tegafur; teloxantronhydrochlorid; temoporfin; teniposid; teroxiron; testolacton; thiamiprin; thioguanin; thiotepa; tiazofurin; tirapazamin; toremi-fencitrat; trestolonacetat; triciribinphosphat; trimetrexat; trimetrexatglucuro-nat; triptorelin; tubulozolhydrochlorid; uracilmustard; uredepa; vapreotid; ver-teporfin; vinblastinsulfat; vincristinsulfat; vindesin; vindesinsulfat; vinepidinsul-fat; vinglycinatsulfat; vinleurosinsulfat; vinorelbintartrat; vinrosidinsulfat; vin-zolidinsulfat; vorozol; zeniplatin; zinostatin; og zorubicinhydrochlorid, 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abirateron; aclarubicin; acylfulven; adecypenol; adozelesin; aldesleukin; ALL-TK-antagonister; alt-retamin; ambamustin; amidox; amifostin; aminolaevulinsyre; amrubicin; am-sacrin; anagrelid; anastrozol; andrographolid; angiogenesehæmmere; antagonist D; antagonist G; antarelix; anti-dorsalizing morfogenetisk protein-l; antiandrogen, prostatakarcinom; antiestrogen; antineoplaston; antisenseolig-onukleotider; aphidicolinglycinat; apoptosegen, modulatorer; apoptoseregula-torer; apurinsyre; ara-CDP-DL-PTBA; arginindeaminase; asulacrin; ata-mestan; atrimustin; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosin; baccatin-lIl-derivater; balanol; batimastat; BCRIABL-antagonister; benzochloriner; benzoylstaurosporin; betalactamderivater; be-ta-alethin; betaclamycin B; betulinsyre; bFGF-hæmmer; bicalutamid; bi- santren; bisaziridinylspermin; bisnafid; bistraten A; bizelesin; breflat; bropiri-min; budotitan; buthioninsulfoximin; calcipotriol; calphostin C; camptothecin-derivater; capecitabin; carboxamid-amino-triazol; carboxyamidotriazol; CaRest M3; CARN 700; brusk-afledt hæmmer; carzelesin; caseinkinase-hæmmere (IcaS); castanospermin; cecropin B; cetrorelix; chloriner; chlorquinoxalinsulfonamid; cicaprost; cis-porphyrin; cladribin; clomifenanalo-ger; clotrimazol; collismycin A; collismycin B; combretastatin A4; combreta-statinanalog; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryp-tophycin-A-derivater; curacin A; cyclopentanthraquinoner; cycloplatam; cy-pemycin; cytarabinocfosfat; cytolytisk faktor; cytostatin; dacliximab; decitabin; dehydrodidemnin B; deslorelin; dexamethason; dexifosfamid; dexrazoxan; dexverapamil; diaziquon; didemnin B; didox; diethylnorspermin; dihydro-5-azacytidin; dihydrotaxol; dioxamycin; diphenylspiromustin; docetaxel; doco-sanol; dolasetron; doxifluridin; doxorubicin; droloxifen; dronabinol; duocarmy-cin SA; ebselen; ecomustin; edelfosin; edrecolomab; eflomithin; elemen; emi-tefur; epirubicin; epristerid; estramustinanalog; estrogenagonister; estrogen-antagonister; etanidazol; etoposidphosphat; exemestan; fadrozol; fazarabin; feuretinid; filgrastim; finasterid; flavopiridol; flezelastin; fluasteron; fludarabin; fluordaunorunicinhydrochlorid; forfenimex; formestan; fostriecin; foternustin; gadoliniumtexaphyrin; galliumnitrat; galocitabin; ganirelix; gelatinasehæmmere; gemcitabin; glutathionhæmmere; hepsulfam; heregulin; hexamethylenbisacetamid; hypericin; ibandronsyre; idarubicin; idoxifen; idramanton; ilmofosin; ilomastat; imatinib (Gleevec®), imiquimod; im-munostimulantpeptider; insulin-lignende vækstfaktor-1 -receptorhæmmer; interferonagonister; interferoner; interleukiner; iobenguan; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladin; isobengazol; isohomohalicondrin B; itase-tron; jasplakinolid; kahalalid F; lamellarin-N-triacetat; laureotid; leinamycin; lenograstim; lentinansulfat; leptolstatin; letrozol; leukæmihæmmende faktor; leukocytalfainterferon; leuprolid+estrogen+progesteron; leuprorelin; levami-sol; liarozol; lineært polyaminanalog; lipofilt disaccharidpeptid; lipofile platinforbindelser; lissoclinamid 7; lobaplatin; lombricin; lometrexol; lonidamin; lo-soxantron; loxoribin; lurtotecan; lutetiumtexaphyrin; lysofyllin; lytiske peptider; maitansin; mannostatin A; marimastat; masoprocol; maspin; matrilysinhæm-mere; matrixmetalloproteinasehæmmere; menogaril; merbaron; meterelin; methioninase; metoclopramid; MIF-hæmmer; mifepriston; miltefosin; miri-mostim; mitoguazon; mitolactol; mitomycinanaloger; mitonafid; mitotoxinfi- broblastvækstfaktor-saporin; mitoxantron; mofaroten; molgramostim; Erbitux, humant choriongonadotrophin; monophosphoryllipid A+mykobakteriecellevæg sk; mopidamol; mustard-anticancermiddel; myca-peroxid B; mykobakterielt cellevægekstrakt; myriaporon; N-acetyldinalin; N-substituerede benzamider; nafarelin; nagrestip; naloxon+pentazocin; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronsyre; nilutamid; nisamycin; nitrorgenoxidmodulatorer; nitroxidantioxidant; nitrullyn; oblimersen (Genasense®); 06-benzylguanin; octreotid; okicenon; oligonuc-leotider; onapriston; ondansetron; ondansetron; oracin; oral cytokininducer; ormaplatin; osateron; oxaliplatin; oxaunomycin; paclitaxel; paclitaxelanaloger; paclitaxelderivater; palauamin; palmitoylrhizoxin; pamidronsyre; panaxytriol; panomifen; parabactin; pazelliptin; pegaspargase; peldesin; pentosanpolysul-fanatrium; pentostatin; pentrozol; perflubron; perfosfamid; perillylalkohol; phenazinomycin; phenylacetat; phosphatasehæmmere; picibanil; pilocarpin-hydrochlorid; pirarubicin; piritrexim; placetin A; placetin B; plasminogenaktivatorhæmmer; platinkompleks; platinforbindelser; platin-triaminkompleks; porfimernatrium; porfiromycin; prednison; propyl bis-acridon; prostaglandin 12; proteasomhæmmere; protein A-baseret immunmodulator; proteinkinase-C-hæmmer; proteinkinase-C-hæmmere, mikroalger; proteintyrosinphosphatasehæmmere; purinnukleo- sidphosphorylashæmmere; purpuriner; pyrazoloacridin; pyridoxyleret hemo-globinpolyoxyethylenkonjugat; raf-antagonister; raltitrexed; ramosetron; ras famesyl-protein-transferase-hæmmere; ras-hæmmere; ras-GAP-hæmmer; retelliptin demethyleret; rhenium Re 186 etidronat; rhizoxin; ribozymer; RII-retinamid; rohitukin; romurtid; roquinimex; rubiginon B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1-mimetika; semustin; senescens-afledt hæmmer 1; senseoligonukleotider; signaltransduktions-hæmmere; sizofiran; sobuzoxan; natriumborocaptat; natriumphenylacetat; solverol; somatomedinbindende protein; sonermin; sparfossyre; spicamycin D; spiromustin; splenopentin; spongistatin 1; squalamin; stipiamid; stromelysinhæmmere; sulfinosin; superaktiv vasoaktiv intestinal peptidantagonist; suradista; suramin; swainsonin; tallimustin; tamoxifenmethiodid; tauromustin; tazaroten; tecogalannatrium; tegafur; tellurapyrylium; telome-rashæmmere; temoporfin; teniposid; tetrachlordecaoxid; tetrazomin; tha-liblastin; thiocoralin; thrombopoietin; thrombopoietinmimetika; thymalfasin; thymopoietinreceptoragonist; thymotrinan; skjoldbruskkirtelstimulerende hormon; tinethyletiopurpurin; tirapazamin; titanocenbichlorid; topsentin; tore-mifen; translationshæmmere; tretinoin; triacetyluridin; triciribin; trimetrexat; triptorelin; tropisetron; turosterid; tyrosinkinasehæmmere; tyrphostiner; UBC-hæmmere; ubenimex; urogenital sinus-afledt væksthæmmende faktor; uroki-nasereceptorantagonister; vapreotid; variolin B; velaresol; veramin; verdiner; verteporfin; vinorelbin; vinxaltin; vitaxin; vorozol; zanoteron; zeniplatin; zilascorb; og zinostatinstimalamer, 2-methoxyestradiol, telomestatin, induce-rofapoptose i myelomatoseceller (som eksempelvis TRAIL), statiner, se-maxanib, cyclosporin, etanercept, doxycyclin, bortezomib, oblimersen (Gen-asense®), remicad, docetaxel, celecoxib, melphalan, dexamethason (Deca-dron®), steroider, gemcitabin, cisplatinum, temozolomid, etoposid, cy-clophosphamid, temodar, carboplatin, procarbazin, gliadel, tamoxifen, topo-tecan, methotrexat, Arisa®, taxol, taxoter, fluoruracil, leucovorin, irinotecan, xeloda, CPT-II, interferonalfa, pegyleret interferonaflfa (f.eks. PEG INTRON-A), capecitabin, cisplatin, thiotepa, fludarabin, carboplatin, liposomaldaunorubicin, cytarabin, doxetaxol, pacilitaxel, vinblastin, IL-2, GM-CSF, dacarbazin, vinorelbin, zoledronsyre, palmitronat, biaxin, busulphan, prednison, bisphosphonat, arsentrioxid, vineristin, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustinnatriumphosphat (Emcyt®), sulindae og etoposid.
9. Farmaceutisk sammensætning ifølge krav 7 eller 8, hvor sammensætningen er formuleret til indgivelse af en enkeltdosis.
10. Farmaceutisk sammensætning ifølge et af kravene 7 til 9, hvor sammensætningen er formuleret som oral, parenteral eller intravenøs dosisform, eventuelt hvor oraldosisformen er en tablet eller kapsel.
11. Forbindelse ifølge et af kravene 1 til 5 til anvendelse i en fremgangsmåde til behandling, håndtering eller forebyggelse af en sygdom eller lidelse, hvor sygdommen eller lidelsen er cancer, en lidelse associeret med angiogenese, smerte, makulær degeneration eller et relateret syndrom, en hudsygdom, en lungelidelse, en asbest-relateret lidelse, en parasitsygdom, en immundefici-ens lidelse, en CNS-lidelse, CNS-skade, aterosklerose eller en relateret lidelse, dysfunktionel søvn eller en relateret lidelse, hæmoglobinopati eller en relateret lidelse eller en TNFa-relateret lidelse.
12. Forbindelse til anvendelse i fremgangsmåden ifølge krav 11, hvor sygdommen er cancer.
13. Forbindelse til anvendelse i fremgangsmåden ifølge krav 12, hvor canceren er hæmatologisk eller solid cancer.
14. Forbindelse til anvendelse i fremgangsmåden ifølge et af kravene 11 til 13, hvilken forbindelse endvidere omfatter indgivelse af et eller flere yderligere aktive midler.
15. Forbindelse til anvendelse i fremgangsmåden ifølge et af kravene 11 til 14, hvor forbindelsen indgives oralt eller parenteralt.
DK09741174.8T 2008-10-29 2009-10-26 Isoindolinforbindelser til anvendelse ved behandling af cancer DK2358697T3 (da)

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