Hydrophilic linkers and their uses for conjugation of drugs to a cell binding molecules

Patent metadata

Field	Value
Publication number	US-10131682-B2
Application number	US-201214432073-A
Country	US
Kind code	B2
Filing date	Nov 24, 2012
Priority date	Nov 24, 2012
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

Cell binding agent-drug conjugates comprising hydrophilic linkers, and methods of using such linkers and conjugates are provided.

First claim

What is claimed is:

1. A hydrophilic linker of formula (I)

wherein:
Y represents a functional group that enables reaction of the hydrophilic linker with a cell-binding agent;
Q and T are either —P(═O)(OM)-, or —S(O 2 )—, or —S(O)—;
m and n are integer from 0 to 5, but not 0 at the same time; provided that when m=1·n=0, Q is not —P(═O)(OM)-; when n=1, m=0, T is not —P(═O)(OM)-; and when Q or T is —S(O 2 )—, m and n are not 0:
Z represents a functional group that enables linkage of the hydrophilic linker to a cytotoxic drug via a disulfide, thioether, thioester, hydrazone, ether, ester, carbamate, carbonate, secondary, tertiary, or quaternary amine, imine, cycloheteroalkane, heteroaromatic, alkoxime or amide bond;
R 1 , R 2 , R 3 , and R 4 , are the same or different and are absent, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether or amide having 2-6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, or combination thereof,
or R 1 , R 2 , R 3 and R 4 are respectively a chain of two or more atoms selected from the group consisting of C, N, O, S, Si, and P that covalently connects a cell-surface binding ligand, a phosphinate or sulfonyl group, a conjugated drug and among themselves (R 1 , R 2 , R 3 and R 4 );
R 5 and R 6 , are the same or different and are absent, H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether or amide having 2-6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, or combination thereof;
M is H, or Na, or K, or N + R 1 R 2 R 3 or a pharmaceutical salt.

2. The hydrophilic linker of claim 1 , wherein Z comprises a thiol, disulfide, amino, carboxy, aldehydes, maleimido, haloacetyl, hydrazine or hydroxyl group.

3. A cell-binding agent-drug conjugate of formula (II):

wherein:
Cb represents a cell-binding agent;
Drug represents a drug linked to the cell-binding agent via the hydrophilic linker by a disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, cycloheteroalkane, heteroaromatic, alkoxime or amide bond;
Q and T are either —P(═O)(OM)-, or —S(O 2 )—, or —S(O)—;
m and n are integer from 0 to 5, but not 0 at the same time; provided that when m=1, n=0, Q is not —P(═O)(OM)-; when n=1, m=0, T is not —P(═O)(OM)-; and when Q or T is —S(O)—, m and n are not 0:
R 1 , R 2 , R 3 , and R 4 , are the same or different and are absent, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether or amide having 2-6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, or combination thereof,
or R 1 , R 2 , R 3 and R 4 are respectively a chain of two or more atoms selected from the group consisting of C, N, O, S, Si, and P that covalently connects a cell-surface binding ligand, a phosphinate or sulfonyl group, a conjugated drug and among themselves (R 1 , R 2 , R 3 and R 4 );
R 5 and R 6 , are the same or different and are absent, H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl, or ester, ether or amide having 2-6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, or combination thereof;
M is H, or Na, or K, or N + R 1 R 2 R 3 or a pharmaceutical salt.

4. The conjugate of claim 3 , wherein the Drug is selected from the group consisting of
1) therapeutic agents comprising
a). Alkylating agents comprising chlorambucil, chlornaphazine, cyclophosphamide, dacarbazine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, mannomustine, mitobronitol, melphalan, mitolactol, pipobroman, novembichin, phenesterine, prednimustine, thiotepa, trofosfamide, uracil mustard, CC-1065 adozelesin, carzelesin, bizelesin, duocarmycin, KW-2189, CBI-TMI, pyrrolobenzodiazepine dimers, tomaymycin dimers, indolinobenzodiazepine dimers, imidazobenzothiadiazepine dimers, oxazolidinobenzodiazepine dimers, carmustine, lomustine, chlorozotocin, fotemustine, nimustine, ranimustine, busulfan, treosulfan, improsulfan piposulfan, Triazenes, dacarbazine, carboplatin, cisplatin, oxaliplatin, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide or trimethylolomelamine1;
b). Plant Alkaloids comprising vincristine, vinblastine, vindesine, vinorelbine, navelbin, paclitaxel, docetaxol, Maytansinoids comprising DM1, DM2, DM3, DM4, DM5, DM6, or DM7, maytansine, ansamitocins, cryptophycin 1, cryptophycin 8, epothilones, eleutherobin, discodermolide, bryostatins, dolostatins, auristatins, tubulysins, cephalostatins, pancratistatin, sarcodictyin A or spongistatin;
c). DNA Topoisomerase Inhibitors comprising 9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoic acids, retinols, teniposide, topotecan, 9-nitrocamptothecin, or mitomycins;
d). Anti-metabolites comprising methotrexate, trimetrexate, denopterin, pteropterin, aminopterin, mycophenolic acid, tiazofurin, ribavirin, EICAR, hydroxyurea, deferoxamine, ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, 5-Fluorouracil, floxuridine, ratitrexed, cytarabine, cytosine arabinoside, fludarabine, azathioprine, fludarabine, mercaptopurine, thiamiprine, thioguanine, and a folic acid replenisher;
e). Hormonal therapies comprising Receptor antagonists comprising Anti-estrogen selected from the group consisting of megestrol, raloxifene, and tamoxifen; LHRH agonists comprising goserelin, and leuprolide acetate; Anti-androgens comprising bicalutamide, flutamide, calusterone, dromostanolone propionate, epitiostanol, goserelin, leuprolide, mepitiostane, nilutamide, testolactone, and trilostane;
f). Vitamin D3 compounds comprising CB 1093, EB 1089 KH 1060, cholecalciferol, or ergocalciferol;
g). Photodynamic therapies comprising verteporfin, phthalocyanine, photo sensitizer Pc4, or demethoxy-hypocrellin A;
h). Cytokines comprising Interferon-alpha, Interferon-gamma, tumor necrosis factor (TNFs), or human proteins containing a TNF domain;
i). Kinase inhibitors comprising, imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, mubritinib, ponatinib, bafetinib, bosutinib, cabozantinib, vismodegib, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, or ispinesib;
j). antibiotics comprising calicheamicin γ1, δ1, α1 or β1, dynemicin A, deoxydynemicin, esperamicin, kedarcidin, C-1027, maduropeptin, neocarzinostatin chromophore, 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, nitomycin

Assignees

• Hangzhou Dac Biotech Co Ltd

Inventors

• Zhao R Yongxin

Classifications

• C07F9/58

  Pyridine rings · CPC title

• C07F9/301

  Acyclic saturated acids which can have further substituents on alkyl · CPC title

• C07F9/65583

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• A61K47/6889

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title