Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule

A cell-binding agent-drug conjugate compound of Formula (II)

• wherein:
• Cb represents a cell-binding agent;
• Drug1 and Drug2 are the same or different and represent cytotoxic agents;
• n is 1˜20;
• R1 and R2 are the same or different, and are absent, a linear alkyl having from 1 to 6 carbon atoms;
• branched or cyclic alkyl having from 3 to 6 carbon atoms;
• linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms;
• ester, ether, or amide having from 2 to 6 carbon atoms;
• or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 1 to about 1000, or a combination thereof;
• and
• X1 and X2 are independently NH, N(R3), O, S or CH2;
• R3 is H, a linear alkyl having from 1 to 6 carbon atoms;
• branched or cyclic alkyl having from 3 to 6 carbon atoms;
• linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms;
• or esters, ether, amide having from 2 to 6 carbon atoms;
• or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 0 to about 1000, or a combination thereof,
• wherein the cell-binding agent is selected from the group consisting of an antibody, a protein, a vitamin, a peptide, a polymeric micelle, a liposome, a lipoprotein-based drug carrier, a nano-particle drug carrier, and a dendrimer, each of which optionally is coated with a cell-binding ligand, and a combination thereof, and
• wherein the cytotoxic agents are selected from the group consisting of:
• 1). chemotherapeutic agents consisting of:
• a). alkylating agents consisting of:
• nitrogen mustards consisting of chlorambucil, chlornaphazine, cyclophosphamide, dacarbazine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, mannomustine, mitobronitol, melphalan, mitolactol, pipobroman, novembichin, phenesterine, prednimustine, thiotepa, trofosfamide, and uracil mustard;
• CC-1065 and adozelesin, carzelesin and bizelesin compounds thereof;
• duocarmycin compounds, KW-2189 and CBI-TMI;
• benzodiazepine dimers consisting of dimers of pyrrolobenzodiazepine or tomaymycin, indolinobenzodiazepines, imidazobenzothiadiazepines, and oxazolidinobenzodiazepines;
• nitrosoureas consisting of carmustine, lomustine, chlorozotocin, fotemustine, nimustine, and ranimustine;
• alkylsulphonates consisting of busulfan, treosulfan, improsulfan and piposulfan;
• triazenes;
• platinum containing compounds consisting of carboplatin, cisplatin, and oxaliplatin;
• aziridines consisting of benzodopa, carboquone, meturedopa, and uredopa;
• ethylenimines and methylamelamines consisting of altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaor-amide and trimethylolomelamine;
• b). plant alkaloids consisting of:
• Vinca alkaloids consisting of vincristine, vinblastine, vindesine, vinorelbine, and navelbin;
• taxoids consisting of paclitaxel, docetaxol, Maytansinoids consisting of DM1, DM2, DM3, DM4, DM5, DM6, DM7, maytansine and ansamitocins, cryptophycins consisting of cryptophycin 1 and cryptophycin 8;
• epothilones, eleutherobin, discodermolide, bryostatins, dolostatins, auristatins, tubulysins, and cephalostatins;
• pancratistatin;
• sarcodictyin;
• and spongistatin;
• c). DNA topoisomerase inhibitors consisting of:
• epipodophyllins consisting of 9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoic acids, teniposide, topotecan, and 9-nitrocamptothecin;
• mitomycins;
• d). antimetabolites consisting of:
• anti-folate:
• DHFR inhibitors consisting of methotrexate, trimetrexate, denopterin, pteropterin, and aminopterin;
• IMP dehydrogenase inhibitors consisting of mycophenolic acid, tiazofurin, ribavirin, and EICAR;
• ribonucleotide reductase inhibitors consisting of hydroxyurea, and deferoxamine;
• pyrimidine compounds consisting of uracil compounds consisting of ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, 5-fluorouracil, floxuridine, and ratitrexed;
• cytosine compounds consisting of cytarabine, cytosine arabinoside, and fludarabine;
• Purine compounds consisting of azathioprine, fludarabine, mercaptopurine, thiamiprine, and thioguanine;
• folic acid replenisher;
• e). hormonal therapies consisting of:
• receptor antagonists consisting of anti-estrogen consisting of:
• megestrol, raloxifene, and tamoxifen;
• LHRH agonists consisting of goscrclin, and leuprolide acetate;
• anti-androgens consisting of bicalutamide, flutamide, calusterone, dromostanolone propionate, epitiostanol, goserelin, leuprolide, mepitiostane, nilutamide, testolactone, and trilostane;
• retinoids/deltoids consisting of Vitamin D3 compounds consisting of CB 1093, EB 1089 KH 1060, cholecalciferol, and ergocalciferol;
• Photodynamic therapies consisting of verteporfin, phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A;
• cytokines consisting of interferon-alpha, interferon-gamma, tumor necrosis factor, and human proteins containing a TNF domain;
• f). kinase inhibitors consisting of BIMW 2992, imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, E7080, mubritinib, ponatinib, bafetinib, bosutinib, cabozantinib, vismodegib, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, Trastuzumab, Ranibizumab, Panitumumab, and ispinesib;
• g). antibiotics consisting of enediyne antibiotics consisting of calicheamicins consisting of calicheamicin γ1, δ1, α1 and β1;
• dynemicin consisting of dynemicin A and deoxydynemicin;
• esperamicin, kedarcidin, C-1027, maduropeptin, and neocarzinostatin chromophore, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin;
• chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, nitomycins, mycophe-nolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin;
• h). Polyketides (acetogenins) consisting of bullatacin and bullatacinone;
• gemcitabine, epoxomicins, bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-9090, stimuvax, allovectin-7, Xegeva, Provenge, Yervoy, isoprenylation inhibitors, dopaminergic neurotoxins, cell cycle inhibitors, actinomycins consisting of actinomycin D, and dactinomycin, bleomycins consisting of bleomycin A2, bleomycin B2, and peplomycin, anthracyclines consisting of daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mtoxantrone, MDR inhibitors, Ca2+ATPase inhibitors, histone deacetylase inhibitors consisting of vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, belinostat, PCI-24781, entinostat, SB939, resminostat, givinostat, AR-42, CUDC-101, sulforaphane, and trichostatin A;
• thapsigargin, celecoxib, glitazones, epigallocatechin gallate, disulfiram, salinosporamide A;
• anti-adrenals consisting of aminoglutethimide, mitotane, and trilostane;
• aceglatone;
• aldophosphamide glycoside;
• aminolevulinic acid;
• amsacrine;
• arabinoside, bestrabucil;
• bisantrene;
• edatraxate;
• defofamine;
• demecolcine;
• diaziquone;
• eflornithine, elfomithine;
• elliptinium acetate, etoglucid;
• gallium nitrate;
• gacytosine, hydroxyurea;
• ibandronate, lentinan;
• lonidamine;
• mitoguazone;
• mitoxantrone;
• mopidamol;
• nitracrine;
• pentostatin;
• phenamet;
• pirarubicin;
• podophyllinic acid;
• 2-ethylhydrazide;
• procarbazine;
• protein-bound polysaccharide;
• razoxane;
• rhizoxin;
• sizofiran;
• spirogermanium;
• tenuazonic acid;
• triaziquone;
• 2, 2′,2″-trichlorotriethylamine;
• trichothecenes consisting of T-2 toxin, verrucarin A, roridin A and anguidine;
• urethane, siRNA, and antisense drugs;
• 2). anti-autoimmune disease agents consisting of:
• cyclosporine, cyclosporine A, aminocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, corticosteroids consisting of amcinonide, betamethasone, budesonide, hydrocortisone, flunisolide, fluticasone propionate, fluocortolone danazol, dexamethasone, triamcinolone acetonide, and beclometasone dipropionate, DHEA, enanercept, hydroxychloroquine, infliximab, meloxicam, methotrexate, mofetil, mycophenylate, prednisone, sirolimus, and tacrolimus;
• 3). anti-infectious disease agents consisting of:
• a). aminoglycosides consisting of:
• amikacin, astromicin, gentamicin consisting of netilmicin, sisomicin, and isepamicin, hygromycin B, kanamycin consisting of amikacin, arbekacin, bekanamycin, dibekacin, and tobramycin, neomycin consisting of framycetin, paromomycin, and ribostamycin, netilmicin, spectinomycin, streptomycin, tobramycin, verdamicin;
• b). amphenicols consisting of azidamfenicol, chloramphenicol, florfenicol, and thiamphenicol;
• c). ansamycins consisting of geldanamycin, and herbimycin;
• d). carbapenems consisting of biapenem, doripenem, ertapenem, imipenem/cilastatin, meropenem, and panipenem;
• e). cephems consisting of carbacephem, cefacetrile, cefaclor, cefradine, cefadroxil, cefalonium, cefaloridine, cefalotin or cefalothin, cefalexin, cefaloglycin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefepime, cefminox, cefoxitin, cefprozil, cefroxadine, ceftezole, cefuroxime, cefixime, cefdinir, cefditoren, cefepime, cefetamet, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefozopran, cephalexin, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefsulodin, ceftazidime, cefteram, ceftibuten, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, cephamycin consisting of cefoxitin, cefotetan, and cefmetazole, oxacephem consisting of flomoxef, and latamoxef;
• f). glycopeptides consisting of bleomycin, vancomycin consisting of oritavancin, and telavancin, teicoplanin, and ramoplanin;
• g). glycylcyclines;
• h). β-lactamase inhibitors consisting of penam consisting of sulbactam, and tazobactam, and clavam;
• i). lincosamides consisting of clindamycin, and lincomycin;
• j). lipopeptides consisting of daptomycin, A54145, and calcium-dependent antibiotics;
• k). macrolides consisting of azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, flurithromycin, josamycin, ketolide consisting of telithromycin, and cethromycin, midecamycin, miocamycin, oleandomycin, rifamycins consisting of rifampicin, rifampin, rifabutin, and rifapentine, rokitamycin, roxithromycin, spectinomycin, spiramycin, tacrolimus, troleandomycin, and telithromycin;
• l). monobac-tams consisting of aztreonam and tigemonam;
• m). oxazolidinones;
• n). penicillins consisting of:
• amoxicillin, ampicillin consisting of pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin, azidocillin, azlocillin, benzylpenicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, clometocillin, procaine benzylpenicillin, carbenicillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, mecillinam, mezlocillin, meticillin, nafcillin, oxacillin, penamecillin, penicillin, pheneticillin, phenoxymethylpenicillin, piperacillin, propicillin, sulbenicillin, temocillin, and ticarcillin;
• o). polypeptides consisting of bacitracin, colistin, and polymyxin B;
• p). quinolones consisting of alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, floxin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, kano trovafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, orbifloxacin, ofloxacin, pefloxacin, trovafloxacin, grepafloxacin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, and trovafloxacin;
• q). streptogramins consisting of pristinamycin, quinupristin and dalfopristin;
• r). sulfonamides consisting of mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole;
• s). steroid antibacterials;
• t). tetracyclines consisting of doxycycline, chlortetracycline, clomocycline, demeclocycline, lymecycline, meclocycline, metacycline, minocycline, oxytetracycline, penimepicycline, rolitetracycline, tetracycline, and glycylcyclines;
• u). antibiotics consisting of annonacin, arsphenamine, bactoprenol inhibitors, DADAL/AR inhibitors, dictyostatin, discodermolide, eleutherobin, epothilone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laulimalide, metronidazole, mupirocin, mycolactone, NAM synthesis inhibitors, nitrofurantoin, paclitaxel, platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampicin (rifampin), tazobactam tinidazole, and uvaricin;
• 4). anti-viral drugs consisting of:
• a). entry/fusion inhibitors consisting of aplaviroc, maraviroc, vicriviroc, gp41, PRO 140, and CD4;
• b). integrase inhibitors consisting of raltegravir, elvitegravir, and globoidnan A;
• c). maturation inhibitors consisting of bevirimat, and vivecon;
• d). neuraminidase inhibitors consisting of oseltamivir, zanamivir, and peramivir;
• e). nucleosides and nucleotides consisting of abacavir, aciclovir, adefovir, amdoxovir, apricitabine, brivudine, cidofovir, clevudine, dexelvucitabine, didanosine, elvucitabine, emtricitabine, entecavir, famciclovir, fluorouracil, 3′-fluoro-substituted 2′,3′-dideoxynucleoside compounds, fomivirsen, ganciclovir, idoxuridine, lamivudine, 1-nucleosides consisting of β-1-thymidine and β-1-2′-deoxycytidine, penciclovir, racivir, ribavirin, stampidine, stavudine, taribavirin, telbivudine, tenofovir, trifluridine valaciclovir, valganciclovir, zalcitabine, and zidovudine;
• f). non-nucleosides consisting of amantadine, ateviridine, capravirine, diarylpyrimidines, delavirdine, docosanol, emivirine, efavirenz, foscarnet, imiquimod, interferon alfa, loviride, lodenosine, methisazone, nevirapine, NOV-205, peginterferon alfa, podophyllotoxin, rifampicin, rimantadine, resiquimod, and tromantadine;
• g). protease inhibitors consisting of amprenavir, atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, pleconaril, ritonavir, saquinavir, telaprevir, and tipranavir;
• h). anti-virus drugs consisting of abzyme, arbidol, calanolide a, ceragenin, cyanovirin-n, diarylpyrimidines, epigallocatechin gallate, foscarnet, griffithsin, taribavirin, hydroxyurea, KP-1461, miltefosine, pleconaril, portmanteau inhibitors, ribavirin, and seliciclib;
• 5). a radioisotope selected from the group consisting of 3H, 11C, 14C, 18F, 32P, 35S, 64Cu, 68Ga, 86Y, 99Tc, 111In, 123I, 124I, 125I, 131I, 133Xe, 177Lu, 211At, and 213Bi;
• 6). a chromophore molecule, which is capable of absorbing a UV light, florescent light, IR light, near IR light, or visual light, and which is selected from the group consisting of xanthophores, erythrophores, iridophores, leucophores, melanophores, cyanophores, fluorophore molecules which are fluorescent chemical compounds re-emitting light upon light, visual phototransduction molecules, photophore molecules, luminescence molecules, luciferin compounds;
• non-protein organic fluorophores consisting of xanthene compounds consisting of fluorescein, rhodamine, Oregon green, eosin, and Texas red;
• cyanine compounds consisting of cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, and merocyanine;
• squaraine compounds and ring-substituted squaraines consisting of Seta, SeTau, and Square dyes;
• naphthalene compounds consisting of dansyl and prodan compounds;
• coumarin compounds;
• oxadiazole compounds consisting of pyridyloxazole, nitrobenzoxadiazole and benzoxadiazole;
• anthracene compounds consisting of anthraquinones consisting of DRAQ5, DRAQ7 and CyTRAK Orange;
• pyrene compounds;
• oxazine compounds consisting of Nile red, Nile blue, cresyl violet, oxazine 170;
• acridine compounds consisting of proflavin, acridine orange, and acridine yellow;
• arylmethine compounds consisting of auramine, crystal violet, and malachite green;
• tetrapyrrole compounds consisting of porphin, phthalocyanine, and bilirubin;
• fluorophore compounds consisting of CF dye, DRAQ and CyTRAK probes, BODIPY, Alexa Fluor, DyLight Fluor, Atto and Tracy, FluoProbes, Abberior Dyes, DY and MegaStokes Dyes, Sulfo Cy dyes, HiLyte Fluor, Seta, SeTau and Square Dyes, Quasar and Cal Fluor dyes, SureLight Dyes, APC, APCXL, RPE, BPE, allophycocyanin, aminocoumarin, APC-Cy7 conjugates, BODIPY-FL, Cascade Blue, Cy2, Cy3, Cy3.5, Cy3B, Cy5, Cy5.5, Cy7, fluorescein, FluorX, hydroxycoumarin, Lissamine Rhodamine B, Lucifer yellow, methoxycoumarin, NBD, Pacific Blue, Pacific Orange, PE-Cy5 conjugates, PE-Cy7 conjugates, PerCP, R-Phycoerythrin, Red 613, Seta-555-Azide, Seta-555-DBCO, Seta-555-NHS, Seta-580-NHS, Seta-680-NHS, Seta-780-NHS, Seta-APC-780, Seta-PerCP-680, Seta-R-PE-670, SeTau-380-NHS, SeTau-405-Maleimide, SeTau-405-NHS, SeTau-425-NHS, SeTau-647-NHS, Texas Red, TRITC, TruRed, X-Rhodamine, 7-AAD, Acridine Orange, Chromomycin A3, CyTRAK Orange, DAPI, DRAQ5, DRAQ7, ethidium bromide, Hoechst33258, Hoechst33342, LDS 751, mithramycin, propidiumlodide, SYTOX Blue, SYTOX Green, SYTOX Orange, thiazole Orange, TO-PRO, cyanine monomer, TOTO-1, TO-PRO-1, TOTO-3, TO-PRO-3, YOSeta-1, YOYO-1;
• and
• 7). a pharmaceutically acceptable salt or acid of any of the above drugs.