Claims for Patent: 10,322,104

Summary for Patent: 10,322,104

Title:	Disulfur bridge linkers for conjugation of a cell-binding molecule
Abstract:	The present invention relates to novel disulfur bridge linkers containing hydrazine used for the specific conjugation of compounds/cytotoxic agents to a cell-binding molecule, through bridge linking a pair of thiols on the cell-binding molecule. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.
Inventor(s):	Zhao; Robert Yongxin (Lexington, MA)
Assignee:	HANGZHOU DAC BIOTECH CO., LTD. (Hangzhou, CN)
Application Number:	15/479,859
Patent Claims:	1. A compound of Formula (IV): ##STR00069## wherein: Drug.sub.1 and Drug.sub.2 are the same or different and 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 molecules thereof; duocarmycin; benzodiazepine dimers; 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 including 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 and 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, cephalostains; pancratistatin; a sarcodictyin; spongistatin; c). DNA topoisomerase inhibitors consisting of Epipodophyllins consisting of 9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoic acids and retinols, teniposide, topotecan, and 9-nitrocamptothecin; mitomycins; d). antimetabolites consisting of anti-folate, DHFR inhibitors consisting of methotrexate, trimetrexate, denopterin, pteropterin, aminopterin and folic acid thereof; IMP dehydrogenase inhibitors consisting of mycophenolic acid, tiazofurin, ribavirin, and EICAR; ribonucleotide, reductase inhibitors consisting of hydroxyurea, and deferoxamine; pyrimidine molecules, uracil molecules consisting of ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, 5-Fluorouracil, floxuridine, and ratitrexed; cytosine molecules consisting of cytarabine, cytosine arabinoside, and fiudarabine; purine molecules consisting of azathioprine, fludarabine, mercaptopurine, thiamiprine, and thioguanine; frolinic acid; 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 molecules 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 (TNF), and human proteins containing a TNF domain; f). kinase inhibitors consisting of anti-EGFR/Erb2, imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, anti-VEGFR2, 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 calicheamicin .gamma.1, .delta.1, .alpha.1 and .beta.1; dynemicin, including dynemicin A and deoxydynemicin; esperamicin, kedarcidin, C-1027, maduropeptin, neocarzinostatin chromophore and chromoprotein enediyne antiobiotic chromomophores, 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, 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, Ca.sup.2+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, 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; PSK.RTM.; 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). .beta.-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, 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). monobactams 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 p consisting of ristinamycin, 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, tazobactam tinidazole, and uvaricin; 4). anti-viral drugs consisting of a). entry/fusion inhibitors consisting of aplaviroc, maraviroc, vicriviroc, enfuvirtide, PRO 140, and ibalizumab; 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 molecules consisting of 3'-fluoro-2',3'-dideoxythymidine and 3'-fluoro-2',3'-dideoxyguanosine, fomivirsen, ganciclovir, idoxuridine, lamivudine, 1nucleosides consisting of .beta.-1-thymidine and .beta.-1-2'-deoxycytidine, penciclovir, racivir, ribavirin, stampidine, stavudine, taribavirin, telbivudine, tenofovir, trifluridine valaciclovir, valganciclovir, zalcitabine, zidovudine; f). non-nucleosides consisting of amantadine, ateviridine, capravirine, diarylpyrimidines consisting of etravirine, and rilpivirine, 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, calanotide 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 .sup.3H, .sup.11C, .sup.14C, .sup.18F, .sup.32P, .sup.35S, .sup.64Cu, .sup.68Ga, .sup.86Y, .sup.99Tc, .sup.111In, .sup.123I, .sup.124I, .sup.125I, .sup.131I, .sup.133Xe, .sup.177Lu, .sup.211At, and .sup.213Bi; 6). a chromophore molecule, which is capable of absorbing a UV light, florescent light, IR light, near IR light, or visual light; and is a class or subclass 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 molecules consisting of fluorescein, rhodamine, Oregon green, eosin, and Texas red; cyanine molecules consisting of cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, and merocyanine; squaraine molecules and ring-substituted squaraines, including Seta, SeTau, and Square dyes; naphthalene molecules consisting of dansyl and prodan molecules; coumarin molecules; oxadiazole molecules consisting of pyridyloxazole, nitrobenzoxadiazole and benzoxadiazole; anthracene molecules consisting of anthraquinones; pyrene molecules; oxazine molecules consisting of Nile red, Nile blue, cresyl violet, and oxazine 170; acridine molecules consisting of proflavin, acridine orange, and acridine yellow; arylmethine molecules consisting of auramine, crystal violet, and malachite green; tetrapyrrole molecules consisting of porphin, phthalocyanine, and bilirubin; fluorophore molecules 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 consisting of APC, RPEPerCP, Phycobilisomes, 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, PropidiumIodide, 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, wherein the fluorophore compounds consist of DCFH, DHR, Fluo-3, Fluo-4, Indo-1, SNARF, Allophycocyanin, AmCyan1, AsRed2, Azami Green, Azurite, B-phycoerythrin, Cerulean, CyPet, DsRed monomer, DsRed2, EBFP, EBFP2, ECFP, EGFP, Emerald, EYFP, GFP, GFP, GFP, GFP, GFP, GFP, GFP, GFPuv, HcRed1, J-Red, Katusha, Kusabira Orange mCFP, mCherry, mCitrine, Midoriishi Cyan, mKate, mKeima-Red, mKO. mOrange, mPlum, mRaspberry, mRFP1, mStrawberry, mTFP1, mTurquoise2, P3, Peridinin Chlorophyll, R-phycoerythrin, T-Sapphire, TagCFP, TagGFP, TagRFP, TagYFP, tdTomato, Topaz, TurboFP602, TurboFP635, TurboGFP, TurboRFP, TurboYFP, Venus, Wild Type GFP, YPet, ZsGreen1, ZsYellow1; and 7). a pharmaceutically acceptable salt or acid of any of the above drugs; Y.sub.1 and Y.sub.2 are the same or different and represent a N-hydroxysuccinimide ester, maleimide, disulfide, haloacetyl, acyl halide(acid halide), ethenesulfonyl, acryl(acryloyl), 2-(tosyloxy)acetyl, 2-(mesyloxy)acetyl, 2-(nitrophenoxy)acetyl, 2-(dinitrophenoxy)acetyl, 2-(fluorophenoxy)-acetyl, 2-(difluorophenoxy)-acetyl, 2-(pentafluorophenoxy)acetyl, 2-(((trifluoromethyl)-sulfonyl)oxy)-acetyl, or an acid anhydride group, as shown below: ##STR00070## N-hydroxysuccinimide ester; ##STR00071## mateimide; ##STR00072## disulfide; ##STR00073## haloacetyl; ##STR00074## acyl halide (acid halide), or an ester, ##STR00075## ethenesulfonyl; ##STR00076## acryl (acryloyl); ##STR00077## 2-(tosyloxy)acetyl; ##STR00078## 2-(mesyloxy)acetyl; ##STR00079## 2-(nitrophenoxy)acetyl; ##STR00080## 2-(dinitrophenoxy)acetyl; ##STR00081## 2-(fluorophenoxy)-acetyl; ##STR00082## 2-(difluorophenoxy)-acetyl; ##STR00083## 2-(pentafluorophenoxy)acetyl; ##STR00084## methylsulfone phenyloxadiazole (ODA); ##STR00085## 2-(((trifluoromethy)-sulfonyl)oxy)acetyl; ##STR00086## acid anhydride, or Y.sub.1 and Y.sub.2 together represent ##STR00087## wherein X.sub.1 is F, Cl, Br, I or Lv; X.sub.2 is O, NH, N(R.sub.1), or CH.sub.2; R.sub.5 is R.sub.1, aromatic, heteroaromatic, or aromatic group wherein one or several H atoms are replaced independently by --R.sub.1, -halogen, --OR.sub.1, --SR.sub.1, --NR.sub.1R.sub.2, --NO.sub.2, --S(O)R.sub.1, --S(O).sub.2R.sub.1, or --COOR.sub.1; is a leaving group selected from nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; monofluorophenol; pentachlorophenal; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxybenzo-triazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3'-sulfonate, an anhydride of --(C(O)OC(O)).sub.1/2--, --C(O)OC(O)CH.sub.3 or --(C(O)OC(O)H; or an intermediate molecule generated from any of the above molecules with a condensation reagent for peptide coupling reactions, or for Mitsunobu reactions; R.sub.1 and R.sub.2 are defined below; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are the same or different, and are: (i) absent, (ii) a linear alkyl having from 1 to 8 carbon atoms, branched or cyclic alkyl having from 3 to 8 carbon atoms, (iii) a linear, branched or cyclic alkenyl or alkynyl having from 2 to 8 carbon atoms, (iv) an ester, ether or amide having 2 to 8 carbon atoms, (v) a polyethyleneoxy unit of formula (OCH.sub.2CH.sub.2).sub.p, wherein p is an integer from 1 to about 1000, or combination thereof; or (vi) a chain of atoms selected from the group consisting of C, N, O, S, Si, and P, which covalently connects to Y.sub.1 or Y.sub.2 and Drug.sub.1 or Drug.sub.2; wherein the condensation reagent for peptide coupling reactions or for Mitsunobu reactions is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, dicyclohexyl-carbodiimide, N,N'-diisopropylcarbodiimide, N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate, 1,1'-carbonyldiimidazole, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, diethyl cyanophosphonate, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 1-[(dimethylamino)(morpholino) methylene]-1H-[1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluorophosphate, 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate, chlorotripyrrolidinophosphonium hexafluorophosphate, fluoro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate, N,N,N',N'-tetramethyl-S-(1-oxido-2-pyridyl)thiuronium hexafluorophosphate, O-(2-oxo-1(2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, S-(1-oxido-2-pyridyl)-N,N,N',N'-tetramethylthiuronium tetrafluoroborate, O-[(ethoxycarbonyl) cyano-methylenaminol]-N,N,N',N'-tetramethyluronium hexafluorophosphate, (1-cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium hexafluoro-phosphate, N-benzyl-N'-cyclohexylcarbodiimide, dipyrrolidino(N-succinimidyloxy)carbenium hexafluoro-phosphate, chlorodipyrrolidinocarbenium hexafluorophosphate, 2-chloro-1,3-dimethyl-imidazolidinium tetrafluoroborate, (benzotriazol-1-yloxyl dipiperidinocarbenium hexafluorophosphate, O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate, bromotris(dimethylamino)-phosphonium hexafluoro-phosphate, propylphosphonic anhydride, 2-morpholinoethyl isocyanide, N,N,N',N'-tetramethyl-O--(N-succinimidyl)nronium hexafluoro-phosphate, 2-bromo-1-ethyl-pyridinium tetrafluoroborate, O[(ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, N,N,N',N'-tetramethyl-O-(N-succinimidyl)uranium tetrafluoroborate, O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N',N'-tetramethyluroniu- m tetrafluoroborate, 1,1'-(azodicarbonyl)dipiperidine, di-(4-chlorobenzyl) azodicarboxylate, di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, or diethyl azodicarboxylate. 2. The compound of claim 1, wherein Drug.sub.1 and Drug.sub.2 are selected from the group consisting of tubulysins, calicheamicins, auristatins, maytansinoids, CC-1065 molecules, daunorubicin and doxorubicin compounds, taxanoids, cryptophycins, epothilones, benzodiazepine dimers consisting of dimers of pyrrolobenzodiazepine, tomaymycin, anthramycin, indolinobenzodiazepines, imidazobenzothiadiazepines, and oxazolidinobenzodiaze-pines, calicheamicins and enediyne antibiotics, actinomycin, azaserines, bleomycins, epirubicin, tamoxifen, idarubicin, dolastatins/auristatins consisting of monomethyl auristatin E, MMAE MMAF, auristatin PYE, auristatin TP, auristatins 2-AQ, 6-AQ, EB, and EFP, duocarmycins, thiotepa, vincristine, hemiasterlins, nazumamides, microginins, radiosumins, alterobactins, microsclerodermins, theonellamides, esperamicins, siRNA, nucleolytic enzymes, and pharmaceutically acceptable salts, and acids of any of the above molecules. 3. The compound of claim 1, wherein Drug.sub.1 and Drug.sub.2 are a chromophore molecule. 4. The compound of claim 1, wherein Drug.sub.1 and Drug.sub.2 are a Tubulysin molecule. 5. The compound of claim 1, wherein Drug.sub.1 and Drug.sub.2 are a Calicheamicin molecule. 6. The compound of claim 1, wherein Drug.sub.1 and Drug.sub.2 are a Maytansinoid molecule. 7. The compound of claim 1, wherein Drug.sub.1 and Drug.sub.2 are a Taxane molecule. 8. The compound of claim 1, wherein Drug.sub.1 and Drug.sub.2 are a CC-1065 molecule or doucarmycin molecule. 9. The compound of claim 1, wherein Drug.sub.1 and Drug.sub.2 are a Daunorubicin or Doxorubicin molecule. 10. The compound of claim 1, wherein Drug.sub.1 and Drug.sub.2 are an auristatin or dolastatin molecule. 11. The compound of claim 1, wherein Drug.sub.1 and Drug.sub.2 are a benzodiazepine dimer molecule. 12. The compound of claim 1, wherein R.sub.1 R.sub.2, R.sub.3 or R.sub.4 is one or more linker components of 6-maleimidocaproyl, maleimido propanoyl, valine-citrulline, alanine-phenylalanine, lysine-phenylalanine, p-aminobenzyloxycarbonyl, 4-thio-pentanoate, 4-(N-maleimidomethyl)cyclo-hexane-1-carboxylate, 4-thio-butyrate, maleimidoethyl, 4-thio-2-hydroxysulfonyl-butyrate, pyridinyl-dithiol, alkoxy amino, ethyleneoxy, 4-methyl-4-dithio-pentanoic, azido, alkynyl, dithio, peptide, or (4-acetyl)aminobenzoate. 13. The compound of claim 1, wherein R.sub.1, R.sub.2, R.sub.3 or R.sub.4 is a peptide of 1 to 20 units of natural or unnatural amino acids, or a p-aminobenzyl unit, or a 6-maleimidocaproyl unit, or a disulfide unit, or a thioether unit, or a hydrozone unit, or a triazole unit, or an alkoxime unit. 14. The compound of claim 1, wherein R.sub.1, R.sub.2, R.sub.3 or R.sub.4 is cleaveable by a protease. 15. The compound of claim 1, wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are respectively a chain of 1 to 500 atoms selected from the group consisting of C, N, O, S, Si, and P. 16. A method for preparing the compound of claim 1, comprising reacting a compound of Formula (I) with a drug or cytotoxic molecule: ##STR00088## wherein Z.sub.1 and Z.sub.2 are the same or different and represent a function group that is capable of reacting with the drug or cytotoxic molecule. 17. A method for preparing a conjugate of a cell-binding molecule with a cytotoxic drug, comprising reacting the compound of claim 1 with a cell-binding molecule having a pair of free thiols.

Details for Patent 10,322,104

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REMICADE	infliximab	For Injection	103772	08/24/1998		2035-07-15
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2035-07-15
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2035-07-15
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2035-07-15