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DK2833973T3 - Forbindelser, der er anvendelige som ATR-kinaseinhibitorer og kombinationsterapier deraf - Google Patents

Forbindelser, der er anvendelige som ATR-kinaseinhibitorer og kombinationsterapier deraf Download PDF

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DK2833973T3
DK2833973T3 DK13728551.6T DK13728551T DK2833973T3 DK 2833973 T3 DK2833973 T3 DK 2833973T3 DK 13728551 T DK13728551 T DK 13728551T DK 2833973 T3 DK2833973 T3 DK 2833973T3
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John Robert Pollard
Philip Michael Reaper
Mohammed Asmal
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Vertex Pharma
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Claims (16)

1. En forbindelse repræsenteret ved den følgende strukturformel:
eller et farmaceutisk acceptabelt salt deraf; i kombination med et yderligere terapeutisk middel, hvor nævnte yderligere terapeutiske middel inhiberer et baseexcisionsreparationsprotein; og hvor basexcisionsreparati-onsproteinet er PARPI eller PARP2; til anvendelse ved a) fremning af celledød i en cancercelle hos en patient eller b) sensibilisering af celler til DNA-skadende midler i en patient,
2. Forbindelse repræsenteret ved den følgende strukturformel:
eller et farmaceutisk acceptabelt salt deraf; i kombination med et yderligere terapeutisk middel, hvor nævnte yderligere terapeutiske middel inhiberer et baseexcisionsreparationsprotein; og hvor basexcisionsreparati-onsproteinet er PARPI eller PARP2; til anvendelse ved behandling af cancer hos en patient.
3. Forbindelse til anvendelse ifølge krav 1 eller 2, hvor forbindelsen er
4. Forbindelse til anvendelse ifølge krav 1 eller 2, hvor forbindelsen er et farmaceutisk acceptabelt salt af
5, Forbindelse eller et farmaceutisk acceptabelt salt deraf til anvendelse ifølge et hvilket som helst af kravene 1-4, hvor: a) nævnte celle er en cancercelle, der har en defekt i ATM-signalkaskaden, eller nævnte cancercelle eller cancer har en defekt i ATM-signalkaskaden; for eksempel hvor nævnte defekt er ændret eksprimering eller aktivitet af et eller flere af følgende: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, H2AX, MCPHi/BRITl, CTIP og SMC1; eller b) hvor nævnte celle er en cancercelle, der eksprimerer et DNA-skadende on-kogen, eller nævnte cancercelle eller cancer eksprimerer et DNA-skadende onkogen; for eksempel, hvor nævnte cancercelle, cancer eller celle har ændret eksprimering eller aktivitet af et eller flere af følgende: K-Ras, N-Ras, Η-Ras, Raf, Myc, Mos, E2F, Cde25A, CDC4, CDK2, Cyclin E , Cyclin A og Rb.
6, Forbindelse eller et farmaceutisk acceptabelt salt deraf til anvendelse ifølge et hvilket som helst af kravene 1-5, hvor nævnte cancer, cancercelle eller celle har en defekt i et baseexcisionsreparationsprotein; og eventuelt hvor baseexcisionsreparationsprote-inet er PARPI eller PARP2.
7, Forbindelse eller et farmaceutisk acceptabelt salt deraf til anvendelse ifølge et hvilket som helst af kravene 1-6, hvor nævnte yderligere terapeutiske middel er Olaparib (også kendt som AZD2281 eller KU-0059436), Iniparib (også kendt som BS1-201 eller SAR240550), Veliparib (også kendt som ABT-888), Rucaparib (også kendt som PF-01367338), CEP-9722, INO-1001, MK-4827, E7016, BMN673 eller AZD2461.
8, Forbindelse repræsenteret ved den følgende strukturformel: eller et farmaceutisk acceptabelt salt deraf;
i kombination med et yderligere terapeutisk middel, hvor nævnte yderligere terapeutiske middel inhiberer et baseexcisionsreparationsprotein; og hvor basexcisionsreparati-onsproteinet er PARPI eller PARP2; til anvendelse a) som en radiosensibilisator eller en kemosensibilisator hos en patient; eller b) ved behandling af en patient, der har cancer med en DNA-skade-respons (DDR)-defekt; for eksempel, hvor nævnte defekt er en mutation eller tab af ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, H2AX, MCPH1/BRIT1, CTIP eller SMC1.
9. Forbindelse til anvendelse ifølge krav 8, hvor forbindelsen er
10, Forbindelse til anvendelse ifølge krav 8, hvor forbindelsen er et farmaceutisk acceptabelt salt af
11. Forbindelse eller et farmaceutisk acceptabelt salt deraf til anvendelse ifølge et hvilket som helst af kravene 8-10, hvor nævnte cancer, cancercelle eller celle har en defekt i et baseexcisionsreparationsprotein; eventuelt hvor baseexeisionsreparations-proteinet er PARPI eller PARP2.
12. Forbindelse eller et farmaceutisk acceptabelt salt deraf til anvendelse ifølge et hvilket som helst af kravene 8-11, hvor nævnte yderligere terapeutiske middel er Olaparib (også kendt som AZD2281 eller KU-0059436), Iniparib (også kendt som BSI-201 eller SAR240550), Veliparib (også kendt som ABT-888), Rueaparib (også kendt som PF-01367338), CEP-9722, INO-1001, MK-4827, E7016, BMN673 eller AZD2461.
13, Forbindelse eller et farmaceutisk acceptabelt salt deraf til anvendelse ifølge et hvilket som helst af kravene 1-7, hvor nævnte celle eller cancercelle er en celle udvalgt blandt gruppen bestående af oralcancercelle, hjertecancercelle, lungecancercelle, gastrointestinalcancercelle, urogenitaleancercelle, levercancercelle, knoglecancercelle, nervesystemcancercelle, gynækologisk cancercelle, hudcancercelle, skjoldbruskkirtel-cancercelle og binyrecancercelle; for eksempel, hvor nævnte celle eller cancercelle er en celle fra en oralcancer udvalgt blandt gruppen bestående af: kindhulrumscancer, læbecancer, tungecancer, mundcancer og faryn-galcaneer; hvor nævnte celle eller cancercelle er en celle fra en hjertecancer udvalgt blandt gruppen bestående af: sarkomer (angiosakromer, fibro s akromer, rhabdomyosakromer, li-posarkomer), myxomer, rhabdomyomer, fibromer, lipomer og teratomer; hvor nævnte celle eller cancercelle er en celle fra en lungecancer udvalgt blandt gruppen bestående af: bronchogene karcinomer (pladecelle, epidermoidkarcinom, udiffe-rentierede småcellekarcinorner, udifferentieret storcellekarcinom, adenokarcinomer), alveolært (bronchiolært) karcinom, bronchial adenom, sarkom, lymfom, chondroma-tøs hamartom og mesotheliom; hvor nævnte celle eller cancercelle er en celle fra en gastrointestinalcancer udvalgt blandt gruppen bestående af: øsophaguscancer (pladecellekarcinom, strubehoved, adenokarcinom, leiomyosakrom, lymfom), mavecancer (karcinom, lymfom, leiomyo-sakroma), pankreascancer (duktal adenokarcinom., insulinom, glucagonom, gastrinom, karcinoid tumor, vipom), tyndtarmscancer (adenokarcinom, lymfom, karcinoid tumor, Karposis sakrom, leiomyom, hemangiom, lipom, neurofibrom, fibrom) tyktarmscancer (adenokarcinom, rørformet adenom, villøs adenom, hamartom, leiomyom), tyktarmscancer, tarmrectumcaneer, kolorektal cancer og rectumcancer; hvor nævnte celle eller cancercelle er en celle Ira en urogenitalcancer udvalgt blandt gruppen bestående af: nyrecancer (adenokarcinom, Wilms tumor [nefroblastom], lymfom), blærecancer, urethralcancer (pladecellekarcinom, transitionalcellekarcinom, adenokarcinom), prostatacancer (adenokarcinom, sarkom) og testikelcancer (semi-nom, teratom, embryonal karcinom, teratokarcinom, choriokarcinom, sarkom, intersti-tialcellekarcinom, fibrom, fibroadenom, adenomatoide tumorer, lipom); hvor nævnte celle eller cancercelle er en celle fra en levercancer udvalgt blandt gruppen bestående af: hepatom (hepatocellulært karcinom), cholangiokarcinom, hepa-toblastom, angiosakrom, hepatocellulært adenom, hæmangiom, og galdevejscancer; hvor nævnte celle eller cancercelle er en celle fra en knoglecancer udvalgt blandt gruppen bestående af: osteogent sarkom (osteosarkom), fibro sarkom, malignt fibrøst histiocytom, chondrosakrom, Ewings sarkom, malignt lymfom. (reticulumcellesar-kom), multipelt myelom, malignt kæmpecelletumor chordom, osteoehronfrom (osteocartilaginous exostoser), godartet chondrom, chondroblastom, chondromyxofibrom, osteoid osteom, og kæmpecelletumorer; hvor nævnte celle eller cancercelle er en celle fra en nervesystemcancer udvalgt blandt gruppen bestående af: kraniecancer (osteom, hemangiom, granulom, xanthom, Fagets knoglesygdom), meningealcancer (meningiom, meningiosakrom, gliomatose), hjerne- cancer (astrocytom, medulloblastom, gliom, ependymom, germinom [pinealom], glioblastom multiform, oligodendrogliom, schwannom, retinoblastom, medfødte tumorer), rygmarvscancer, neurofibrom, meningiom, gliom og sarkom; hvor nævnte celle eller cancercelle er en celle fra en gynækologisk cancer udvalgt blandt gruppen bestående af: livmodercancer (endometrisk kareinom), livmoderhalscancer (cervikal kareinom, cervical dysplasi forud for tumor), ovariecancer (ovarie-karcinom [serøst cystadenokarcinom, mueinøse cystadenokarcinom, uklassificeret kareinom], granulosathecal celletumorer, Sertoli-Leydig-celletumorer, dysgerminom, malignt teratom), vulvacancer (pladecellekarcinom, intraepithelialkarcinom, adenokarcinom, fibrosakrom, melan om), vaginalcancer (lyse-celler kareinom, pladecellekarcinom, botryoid sarkom (embryonal rhabdomyosakrom), æggeledercancer (kareinom) og brystcancer; hvor nævnte celle eller cancercelle er en celle fra en hudcancer udvalgt blandt gruppen bestående af: malignt melanom, basalcellekarcinom, pladecellekarcinom, Karposis sarkom, keratoacanthom, dysplastisk nævus, lipom, angiom og dermatofibrom; hvor nævnte celle eller cancercelle er en celle fra en skjoldbruskkirtelcancer udvalgt blandt gruppen bestående af: papillær thyroidkarcinom, follikulært thyroidkarcinom, medullær thyroidkarcinom, multipel endokrin neoplasi type 2A, multipel endokrin neoplasi type 2R, arvelig medullær thyroideancer, feokromocytom og paragangliom; oe hvor nævnte celle eller cancercelle er en celle fra en binyrercancer og eventuelt hvor nævnte binyrecancer er neuroblastom; for eksempel, hvor nævnte celle eller cancercelle er en celle fra lungecancer eller bugspytkirtelcancer; hvor nævnte celle eller cancercelle er en celle fra en lungecancer, hoved- og halscancer, bugspytkirtelcancer, gastrisk cancer eller hjernecancer; eller hvor nævnte celle eller cancercelle er en celle fra en ikke-småcellet lungecancer, småcellet lungecancer, bugspytkirtelcancer, galdevejscancer, hoved- og halscancer, blærecancer, kolorektal cancer, glioblastom, esophageal cancer, brystcancer, hepatocellulært kareinom. eller ovariecancer.
14. Forbindelse eller et farmaceutisk acceptabelt salt deraf til anvendelse ifølge et hvilket som helst af kravene 8-12, hvor nævnte cancer er en fast tumor udvalgt blandt gruppen bestående af oralcancer, hjertecancer, lungecancer, gastrointestinalcancer, urogenitalcancer, levercancer, knoglecancer, nervesystemcancer, gynækologisk cancer, hudcancer, skjoldbruskkirtelcaneer og binyrecancer; for eksempel, hvor nævnte cancer er oralcancer udvalgt blandt gruppen bestående af: kindhulrumscancer, læbecancer, tungecancer, mundcancer og faryngalcancer; hvor nævnte cancer er hjertecancer udvalgt blandt gruppen bestående af: sarkomer (angiosakromer, fibro s akromer, rhabdomyosakromer, liposarkomer), myxomer, rhab-domyomer, fibromer, lipomer og teratomer; hvor nævnte cancer er lungecancer udvalgt blandt gruppen bestående af: broncho gene karcinomer (pladecelle, epidermoid, udifferentierede småcelle, udifferentieret storcelle, adenokarcinomer), alveolært (bronchiolært) karcinom, bronchial adenom, sarkom, lymfom, chondromatøs hamartom og mesotheliom; hvor nævnte cancer er gastrointestinalcancer udvalgt blandt gruppen bestående af: øsophaguscancer (pladecellekarcinom, strubehoved, adenokarcinom, leiomyosakrom, lymfom), mavecancer (karcinom, lymfom, leiomyosakroma), pankreascancer (duktal adenokarcinom, insulinom, glucagonom, gastrinom, karcinoid tumor, vipom), tyndtarmscancer (adenokarcinom, lymfom, karcinoid tumor, Karposis sakrom, leiomyom, hemangiom, lipom, neurofibrom, il brorn s tyktarmscancer ( adenokarcinom, rørformet adenom, villøs adenom, hamartom, leiomyom), tyktarmscancer, tarmrectumcancer, kolorektal cancer og reetumcancer; hvor nævnte cancer er urogenitalcancer udvalgt blandt gruppen bestående af: nyrecancer (adenokarcinom, Wilms tumor [nefroblastom], lymfom), blærecancer, urethralcancer (pladecellekarcinom, transitionaleellekarcinom, adenokarcinom), pro-statacancer (adenokarcinom, sarkom) og testikelcancer (seminom, teratom, embryonal karcinom, teratokarcinom, choriokarcinom, sarkom, interstitialcellekarcinom, fibrom, fibroadenom, adenoma toide tumorer, lipom); hvor nævnte cancer er levercancer udvalgt blandt gruppen bestående af: hepatom (he-patocellulært karcinom), cholangiokareinom, hepatoblastom, angiosakrom, hepatocel-lulært adenom, ha: man gi om, og galdevejscancer; hvor nævnte cancer er knoglecancer udvalgt blandt gruppen bestående af: osteogent sarkom (osteo s arkom), fibrosarkom, malignt fibrøst histiocytom, chondrosakrom, Ewings sarkom, malignt lymfom (retieulumcellesarkom), multipelt myelom, malignt kæmpecelletumor chordom, osteochronfrom (osteocartilaginous exostoser), godartet chondrom, chondroblastom, chondromyxofibrom, osteoid osteom, og kæmpecelletumorer; hvor nævnte cancer er nervesystemcancer udvalgt blandt gruppen bestående af: kraniecancer (osteom, hemangiom, granulom, xanthom, Fagets knoglesygdom), menin-gealcancer (meningiom, meningiosakrom, gliomatose), hjemecancer (astrocytom, medulloblastom, gliom, ependymom, germinom [pinealom], glioblastom multiform, oligodendrogliom, schwannom, retinoblastom, medfødte tumorer), rygmarv'seancer, neurofibrom, meningiom, gliom og sarkom; hvor nævnte cancer er gynækologisk cancer udvalgt blandt gruppen bestående af: livmodercancer (endometrisk karcinom), livmoderhalscancer (cervikal karcinom, cervical dysplasi forud for tumor), ovariecancer (ovariekarcinom [serøst cystadenokarci-nom, mueinøse cystadenokarcinom, uklassificeret karcinom], granulosathecal celle-tumorer, Sertoli-Leydig-celietumorer, dysgerminom, malignt teratom), vulvacancer (pladecellekarcinom, intraepithelialkarcinom, adenokarcinom, fibrosakrom, mela-nom), vaginalcancer (lyse-celler karcinom, pladecellekarcinom, botryoid sarkom (embryonal rhabdomyosakrom), æggeledercancer (karcinom) og brystcancer; hvor nævnte cancer er hudcancer udvalgt blandt gruppen bestående af: malignt rnela-nom, basalcellekarcinom, pladecellekarcinom, Karposis sarkom, keratoacanthom, dysplastisk nævus, lipom, angiom og dermatofibrom; hvor nævnte cancer er skjoldbruskkirteicancer udvalgt blandt gruppen bestående af: papillær thyroidkarcinom, foliikulært thyroidkarcinom, medullær thyroidkarcinom, multipel endokrin neoplasi type 2A, multipel endokrin neoplasi type 2B, arvelig medullær thyroidcancer, feokromocytom og paragangliom; og hvor nævnte cancer er binyrercancer og eventuelt hvor nævnte binyrecancer er neuro-blastom; for eksempel, hvor nævnte cancer er lungecancer eller bugspytkirtelcancer; hvor nævnte cancer er lungecancer, hoved- og halscancer, bugspytkirtelcancer, gastrisk cancer eller hjernecancer; eller hvor nævnte cancer er ikke-småeellet lungecancer, småcellet lungecancer, bugspytkirtelcancer, galdevejscancer, hoved- og halscancer, blærecancer, kolorektal cancer, glioblastom, esophageal cancer, brystcancer, he-patocellulært karcinom eller ovariecancer,
15. Forbindelse eller et farmaceutisk acceptabelt salt deraf til anvendelse til behandling af cancer ifølge et hvilket som helst af krav 2-7, hvor nævnte cancer er en fast tumor udvalgt blandt gruppen bestående af oralcancer, hjertecancer, lungecancer, ga-strointestinaleancer, urogenitalcancer, levercancer, knoglecancer, nervesystemcancer, gynækologisk cancer, hudcancer, skjoldbruskkirtelcancer og binyrecancer; for eksempel, hvor nævnle cancer er oralcancer udvalgt blandt gruppen bestående af: kindhulrumscancer, læbecancer, tungecancer, mundcancer og faryngalcancer; hvor nævnte cancer er hjertecancer udvalgt blandt gruppen bestående af: sarkomer (angiosakromer, fibro s akromer, rhabdomyosakromer, liposarkomer), myxomer, rhab-domyomer, fibromer, lipomer og teratomer; hvor nævnte cancer er lungecancer udvalgt blandt gruppen bestående af: broncho gene karcinomer (pladecelle, epidermoid, udifferentierede småcelle, udifferentieret storcelle, adenokarcinomer), alveolært (bronchiolært) karcinom, bronchial adenom, sarkom, lymfom, chondromatøs hamartom og mesotheiiom; hvor nævnte cancer er gastrointestinalcancer udvalgt blandt gruppen bestående af: øsophaguscancer (pladecellekarcinom, strubehoved, adenokarcinom, leiomyosakrom, lymfom), maveeancer (karcinom, lymfom, leiomyosakroma), pankreascancer (duktal adenokarcinom, insulinom, glueagonom, gastrinom, karcinoid tumor, vipom), tyndtarmscancer (adenokarcinom, lymfom, karcinoid tumor, Karposis sakrom, leiomyom, hemangiom, lipom, neurofibrom, fibrom) tyktarmscancer (adenokarcinom, rørformet adenom, villøs adenom, hamartom, leiomyom), tyktarmscancer, tarmrectumcancer, kolorektal cancer og rectumcancer; hvor nævnte cancer er uro genitalcancer udvalgt blandt gruppen bestående af: nyrecancer (adenokarcinom, Wilms tumor [nefroblastom], lymfom), blærecancer, urethralcancer (pladecellekarcinom, transitionalcellekarcinom, adenokarcinom), pro-statacancer (adenokarcinom, sarkom) og testikelcancer (seminom, teratom, embryonal karcinom, teratokarcinom, choriokarcinom, sarkom, interstitialcellekarcinom, fibrom, fibroadenom, adenoma toide tumorer, lipom); hvor nævnte cancer er levercancer udvalgt blandt gruppen bestående af: hepatom (he-patocellulært karcinom), cholangiokarcinom, hepatoblastom, angiosakrom, hepatocel-lulært adenom, ha: man gi om, og galdevejscancer; hvor nævnte cancer er knoglecancer udvalgt blandt gruppen bestående af: osteogent sarkom (osteosarkom), fibrosarkom, malignt fibrøst histiocytom, chondrosakrom, Ewings sarkom, malignt lymfom (retieulumcellesarkom), multipelt myelom, malignt kæmpecelletumor chordom, osteochronfrom (osteocartilaginous exostoser), godartet chondrom, chondroblastom, chondromyxofibrom, osteoid osteom, og kæmpecelletumorer; hvor nævnte cancer er nervesystemcancer udvalgt blandt gruppen bestående af: kraniecancer (osteom, hemangiom, granulom, xanthom, Fagets knoglesygdom), menin-gealcancer (meningiom, meningiosakrom, gliomatose), hjemecancer (astrocytom, medulloblastom, gliom, ependymom, germinom [pinealom], glioblastom multiform, oligodendrogliom, schwannom, retinoblastom, medfødte tumorer), rygmarv'seancer, neurofibrom, meningiom, gliom og sarkom; hvor nævnte cancer er gynækologisk cancer udvalgt blandt gruppen bestående af: livmodercancer (endometrisk karcinom), livmoderhalscancer (cervikal karcinom, cervical dysplasi forud for tumor), ovariecancer (ovariekarcinom [serøst cystadenokarci-nom, mueinøse cystadenokarcinom, uklassificeret karcinom], granulosathecal celle-tumorer, Sertoli-Leydig-celletumorer, dysgerminom, malignt teratom), vulvacancer (pladecellekarcinom, intraepithelialkarcinom, adenokarcinom, fibrosakrom, mela-nom), vaginalcancer (lyse-celler karcinom, pladecellekarcinom, botryoid sarkom (embryonal rhabdomyosakrom), æggeledercancer (karcinom) og brystcancer; hvor nævnte cancer er hudcancer udvalgt blandt gruppen bestående af: malignt rnela-nom, basalcellekarcinom, pladecellekarcinom, Karposis sarkom, keratoacanthom, dysplastisk nævus, lipom, angiom og dermatofibrom; hvor nævnte cancer er skjoldbruskkirteicancer udvalgt blandt gruppen bestående af: papillær thyroidkarcinom, follikulært thyroidkarcinom, medullær thyroidkarcinom, multipel endokrin neoplasi type 2A, multipel endokrin neoplasi type 2B, arvelig medullær thyroidcancer, feokromocytom og paragangliom; og hvor nævnte cancer er binyrercancer og eventuelt hvor nævnte binyrecancer er neuro-blastom; for eksempel, hvor nævnte cancer er lungecancer eller bugspytkirtelcancer; hvor nævnte cancer er lungecancer, hoved- og halscancer, bugspytkirtelcancer, gastrisk cancer eller hjernecancer; eller hvor nævnte cancer er ikke-småeellet lungecancer, småcellet lungecancer, bugspytkirtelcancer, galdevejscancer, hoved- og halscancer, blærecancer, kolorektal cancer, glioblastom, esophageal cancer, brystcancer, he-patocellulært karcinom eller ovariecancer,
16. Forbindelse eller et farmaceutisk acceptabelt salt deraf til anvendelse ifølge et hvilket som helst af kravene 1-15, i kombination med et DNA-skadende middel: hvor nævnte DNA-skadende middel er passende til den sygdom, der behandles; og nævnte DNA-skadende middel er sammen med nævnte forbindelse som en enkeltdoseringsform eller separat fra nævnte forbindelse som del af en multipel doseringsform; for eksempel, hvor nævnte DNA-skadende middel er kemoterapi eller strålebehandling; eventuelt, hvor nævnte DNA-skadende middel er ioniserende stråling, radiomimetisk neocarzinostatin, et platinationsmiddel (platinating agent), en Topo I-inhibitor, en Topo ΪΪ-inhibitor, en antimetabolit, et alkylerende middel, et alkyl sulf onat eller et antibiotikum; for eksempel, hvor platinationsmiddel er cisplatin, oxaliplatin, carboplatin, nedaplatin, Lobaplatin, triplatintetranitrat, picoplatin, satraplatin, prol indac eller arop-latin; nævnte Topo I inhibitor er camptothecin, topotecan, irinotecan/SN38, rubitecan eller belotecan; nævnte Topo II inhibitor er etoposid, daunorubicin, doxorubicin, acla-rubicin, epirubicin, idarabicin, amrubicin, pirarubicin, valrubicin, zorubicin eller teni-posid; nævnte antimetabolit er aminopterin, methotrexat, pemetrexed, raltitrexed, pen-tostatin, cladribin, clofarabin, fludarabin, thioguanin, mercaptopurin, 6-mercaptopurin, fluorouracil, 5-fluorouracil, capecitabin, tegafur, carmofur, floxuridin, cytarabin, gemcitabin, azacitidin eller hydroxyurinstof; nævnte alkylerende middel er udvalgt blandt gruppen bestående af kvælstofsennep, nitrosoureer, triazener, alkylsulfonater, procarbazin, aziridiner; mechlorethamin, cyclophosphamid, ifosfamid, trofosfamid, chlorambucil, melphalan, prednimustin, bendamustin, uramustin, estramustin, carmu-stin, lomustin, semustin, fotemustin, nimustin, ranimustin, streptozocin, busulfan, mannosulfan, treosulfan, carboquon, thioTEPA, triaziquon, triethylenmelamin, pro-carbazin, dacarbazin, temozolomid, altretamin og mitobronitol; og nævnte antibiotikum er udvalgt blandt gruppen bestående af hydroxyurea, anthracyeliner, anthracen-dioner, antibiotika fra familien Streptomyces, actinomycin, bleomycin, mitomycin og plicamycin; for eksempel, hvor nævnte DNA-skadende middel er et eller flere af følgende: cisplatin, carboplatin, gemcitabin, etoposid, temozolomid og ioniserende stråling.
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