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WO2018182341A1 - Précurseur dimère de pyrrolobenzodiazépine et composé conjugué ligand-lieur associé - Google Patents

Précurseur dimère de pyrrolobenzodiazépine et composé conjugué ligand-lieur associé Download PDF

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Publication number
WO2018182341A1
WO2018182341A1 PCT/KR2018/003744 KR2018003744W WO2018182341A1 WO 2018182341 A1 WO2018182341 A1 WO 2018182341A1 KR 2018003744 W KR2018003744 W KR 2018003744W WO 2018182341 A1 WO2018182341 A1 WO 2018182341A1
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substituted
compound
unsubstituted
alkyl
mmol
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English (en)
Korean (ko)
Inventor
송호영
김성민
김형래
박경은
정철웅
박윤희
최효정
이수인
백주열
이현정
이주영
오지혜
채제욱
오영수
김용주
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Ligachem Biosciences Inc
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Legochem Biosciences Inc
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Priority to EP18774896.7A priority Critical patent/EP3604311A4/fr
Priority to JP2019515212A priority patent/JP7664680B2/ja
Priority to NZ757701A priority patent/NZ757701B2/en
Priority to CA3058360A priority patent/CA3058360A1/fr
Priority to BR112019020136-0A priority patent/BR112019020136B1/pt
Priority to MX2019011655A priority patent/MX2019011655A/es
Priority to IL269535A priority patent/IL269535B2/en
Priority to CN201880003365.6A priority patent/CN109790171B/zh
Priority to AU2018246806A priority patent/AU2018246806B2/en
Priority to US16/328,256 priority patent/US11654197B2/en
Application filed by Legochem Biosciences Inc filed Critical Legochem Biosciences Inc
Priority claimed from KR1020180036895A external-priority patent/KR101938800B1/ko
Publication of WO2018182341A1 publication Critical patent/WO2018182341A1/fr
Anticipated expiration legal-status Critical
Priority to US18/113,948 priority patent/US12398124B2/en
Priority to JP2023081396A priority patent/JP2023113699A/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68035—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to pyrrolobenzodiazepine dimer precursors and their ligand-linker conjugate compounds, compositions containing them, and in particular for their therapeutic use as anticancer agents.
  • Pyrrolobenzodiazepine is known as a natural substance with antibiotic or anti-tumor activity, produced by various actinomycetes. Pyrrolobenzodiazepine is a sequence selective DNA alkylated anticancer agent that covalently binds to cellular DNA. Pyrrolobenzodiazepine, a DNA-crosslinking agent, is known to exhibit significantly stronger anticancer activity than systemic chemotherapeutic agents and can prevent the division of cancer cells without destroying DNA helix.
  • Pyrrolobenzodiazepine has the following general structure:
  • the pyrrolobenzodiazepines differ in the number, type and position of substituents on the aromatic rings A and pyrrolo C rings, and the saturation of the C rings.
  • Some pyrrolobenzodiazepine dimers are undergoing Phase I clinical trials with SGN-CD123A from Seattle Genetics for acute myelocytic leukemia (AML) as a dPBD conjugate for acute myeloid leukemia (AML) disease.
  • AML acute myelocytic leukemia
  • Koltan Pharmaceuticals and Genentech / Roche are known to develop antibody-drug conjugates using pyrrolobenzodiazepine as a cytotoxic drug.
  • Spirogen has developed a technology for treating acute myeloid leukemia based on pyrrolobenzodiazepine.
  • published patents (medyok limited, patent document 1) on pyrrolobenzodiazepine and conjugates thereof, published patents (medyzeb limited, patent document 2) on asymmetric pyrrolobenzodiazepine dimers for the treatment of proliferative diseases, blood Registered patent (medium shock, patent document 3) regarding rolobenzodiazepine, registered patent (medium shock, patent document 4) regarding pyrrolobenzodiazepine for the treatment of proliferative disease, and open patent (mediponate limited, Patent document 5) and the registered patent (spirogen limited, patent document 6) regarding a pyrrolobenzodiazepine exist.
  • the anti-tumor activity is enhanced by modifying the pyrrolobenzodiazepine compound structure, or the anti-cancer activity can be enhanced by administering the pyrrolobenzodiazepine compound having such a modified structure in the form of an antibody-drug conjugate. It only starts.
  • the antibody-drug conjugate having a form linked to carbamate with respect to the form of pyrrolobenzodiazepine dimer, and a cytosol having low cytotoxicity by making the pyrrolobenzodiazepine compound in monomer form into a precursor form There are papers on which it appears that there are research papers on the preparation and activity of N10- (4-nitrobenzyl) carbamate-protected pyrrolobenzodiazepine precursors (Non-Patent Documents 7, Non-Patent Documents 8 and 9). Reference).
  • ADCs antibody-drug conjugates
  • antibody-drug conjugates consist of "antibody-linker-small molecule drugs (toxins)".
  • the linker is not only a functional role that connects the antibody and the drug, but also reaches the target cell stably during the body circulation, and then the drug enters the cell and dissociates between the antibodies and the drug (eg, the result of hydrolysis by enzymes). By dropping the drug well to target cancer cells should be effective. That is, the linker plays a very important role in terms of safety, such as the efficacy of the antibody-drug conjugate and systemic toxicity, depending on the stability of the linker (Discovery Medicine 2010, 10 (53): 329-39).
  • the inventors of the present invention have developed a linker comprising an effective self-immolative group which is more stable in plasma, stable even in the body circulation, and which drug can be easily released in cancer cells to exhibit efficacy.
  • Patent has been secured (Korean Patent No. 1,628,872, etc.).
  • Patent Document 1 Korean Patent Publication No. 2013-0040835 (published April 24, 2013)
  • Patent Document 2 Korean Patent Publication No. 2011-0075542 (Published June 30, 2011)
  • Patent Document 3 Korean Registered Patent No. 1,700,460 (January 20, 2017 registration)
  • Patent Document 4 Korean Registered Patent No. 1,687,054 (registered Dec. 9, 2016)
  • Patent Document 5 Korean Patent Publication No. 2015-0016245 (published Feb. 11, 2015)
  • Patent Document 6 Korean Patent No. 1,059,183 (August 18, 2011)
  • Patent Document 7 PCT / US2016 / 063564
  • Patent Document 8 PCT / US2016 / 063595
  • Patent Document 9 Korean Patent Publication No. 2014-0035393 (published March 21, 2014)
  • Patent Document 10 WO 2017/160569 (Published Sept. 21, 2017)
  • Patent Document 11 US Patent 8,697,688 (April 15, 2014 registration)
  • Patent Document 12 US Patent 9,713,647 (July 25, 2017 registration)
  • Patent Document 13 United States Patent Publication 2015-0283258 (2015.10. 8. publication)
  • Non-Patent Document 1 Kemp Gary C et al., Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin, Bioorganic & Medicinal Chemistry Letters Vol. 27 No. 5, 1154-1158 (2017)
  • Non-Patent Document 2 Julia Mantaj et al., From Anthramycin to Pyrrolobenzodiazepine (PBD) -Containing Antibody-Drug Conjugates (ADCs), Angewandte Chemie International Edition Vol. 56 No. 2, 462-488 (2017)
  • Non-Patent Document 3 Giddens Anna C. et al., Analogues of DNA minor groove cross-linking agents incorporating aminoCBI, an amino derivative of the duocarmycins: Synthesis, cytotoxicity, and potential as payloads for antibody-drug conjugates, Bioorganic & Medicinal Chemistry Vol. 24 No. 22, 6075-6081 (2016)
  • Non-Patent Document 4 Hartley, JA, The development of pyrrolobenzodiazepines as antitumour agents, EXPERT OPIN INV DRUG, 20 (6) 733-744 (2011)
  • Non-Patent Document 5 Kamal Ahmed et al., Synthesis, anticancer activity and mitochondrial mediated apoptosis inducing ability of 2,5-diaryloxadiazole-pyrrolobenzodiazepine conjugates, Bioorganic & Medicinal Chemistry Vol. 18 No. 18, 6666-6677 (2010)
  • Non-Patent Document 6 Guichard S.M et al., Influence of P-glycoprotein expression on in vitro cytotoxicity and in vivo antitumour activity of the novel pyrrolobenzodiazepine dimer SJG-136, European Journal of Cancer Vol. 41 No. 12, 1811-1818 (2005)
  • Non-Patent Document 7 Zhang, Donglu et al, Linker Immolation Determines Cell Killing Activity of Disulfide-Linked Pyrrolobenzodiazepine Antibody-Drug Conjugates, ACS Medicinal Chemistry Letters, 7 (11), 988-993 (2016)
  • Non-Patent Document 8 Masterson, Luke A. et al., Synthesis and biological evaluation of novel pyrrolo [2,1-c] [1,4] benzodiazepine prodrugs for use in antibody directed enzyme prodrug therapy, Bioorganic & Medicinal Chemistry Letters , 16 (2), 252-256 (2006)
  • Non-Patent Document 9 Sangnou, M. J. et al., Design and synthesis of novel pyrrolobenzodiazepine (PBD) prodrugs for ADEPT and GDEPT, Bioorganic & Medicinal Chemistry Letters, 10 (18), 2083-2086 (2000)
  • Non-Patent Document 10 Nature Rev. Cancer 2005, 5 (5), pp. 405-12; Nature Chemical Biology, 2010, 17, pp. 498-506; Lane KT, Bees LS, Structural Biology of Protein of Farnesyltransferase and Geranylgeranyltransferase Type I, Journal of Lipid Research, 47, pp. 681-699 (2006); Patrick J. Kasey, Miguel C. Seabra; Protein Prenyltransferases, The Journal of Biological Chemistry, Vol. 271, No. 10, Issue of March 8, pp. 5289-5292 (1996)
  • Non-Patent Document 11 Benjamin P. Duckworth et al, Chem Bio Chem 2007, 8, 98; Uyen T. T. Nguyen et al, Chem Bio Chem 2007, 8, 408; Guillermo R. Labadie et al, J. Org. Chem. 2007, 72 (24), 9291; James W. Wollack et al, Chem BioChem 2009, 10, 2934
  • Non-Patent Document 13 Berge, et al., J. Pharm. Sci., 66, 1-19 (1977)
  • a pyrrolobenzodiazepine dimer precursor of a novel structure that can increase the blood stability of the pyrrolobenzodiazepine having a low blood stability after administration.
  • the pyrrolobenzodiazepine dimer precursor is further stabilized in the plasma and stable in the body circulation, by incorporating a linker technology comprising a self-immolative group which can be easily released in cancer cells to maximize the efficacy.
  • the present invention aims to provide a drug precursor-linker-ligand system that can stably reach target cells to effectively exert its effect while significantly lowering toxicity.
  • the present invention relates to pyrrolobenzodiazepine dimer prodrugs, pharmaceutically acceptable salts or solvates thereof.
  • R, and R ' are each independently H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NHNH 2, halo, substituted or unsubstituted C 1- 8 alkyl, substituted or unsubstituted C 3- 8 cycloalkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8 alkylthio, substituted or unsubstituted C 3- 20 heteroaryl, substituted or unsubstituted and 1- or di -C 8 alkylamino, - C 20 aryl or 5- mono-
  • C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 3-20 heteroaryl, C 5-20 aryl is substituted, H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NNH 2, halo, C 1-6 alkyl, C 1- 6 alkoxy, C 6- 12 aryl is optionally substituted with substituents selected from the group consisting of,
  • a pyrrolobenzodiazepine dimer precursor is provided.
  • it is necessary to be converted into a valid drug by an additional reaction upon exposure to blood, thereby preventing the possibility of side effects that may occur during unexpected decomposition of the linker, Toxicity to normal cells is reduced, and the drug is more stable than conventional PBD drugs in that the drug is more stable.
  • the antibody-drug conjugate prepared by the conventional method in the production of the antibody-drug conjugate has a high impurity content and exposed imine groups may be attacked by nucleophiles, resulting in the formation of a drug having an unwanted structure.
  • the antibody-drug conjugate prepared by the method according to the present invention has an advantage of high purity and easy separation, and physical properties have been improved as compared with conventional PBD or PBD dimer.
  • the pyrrolobenzodiazepine dimer precursor has the structure of formula (Ia) or (Ia '),
  • Dashed lines indicate any presence of a double bond between C1 and C2, or C2 and C3,
  • R m ' is selected from the group consisting of R m , CO 2 R m , COR m , CHO, CO 2 H, and halo,
  • R m is a substituted or unsubstituted C 1- 12 alkyl, substituted or unsubstituted C 2- 12 alkenyl, substituted or unsubstituted C 2- 12 alkynyl, substituted or unsubstituted C 5- 20 aryl, substituted or unsubstituted C 5- 20 heteroaryl, substituted or unsubstituted C 3- 6 cycloalkyl, substituted or unsubstituted 3 to 7-membered heterocyclyl, substituted or unsubstituted 3 to 7-membered Heterocycloalkyl, and substituted or unsubstituted 5 to 7-membered heteroaryl;
  • C 1- 12 alkyl, C 1- 12 alkoxy, C 2- 12 alkenyl, C 2- 12 alkynyl, C 5- 20 aryl, C 5- 20 heteroaryl, C 3- 6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered-heterocycloalkyl, or 5 to 7 each of the hydrogen atoms of the member heteroaryl are each independently a C 1- 12 alkyl, C 2- 12 alkenyl, C 2- 12 alkynyl, from 5- C 20 aryl, C 5- 20 heteroaryl, C 3- 6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, and 5 to 7 membered heteroaryl group, consisting of Substituted with any one or more selected;
  • R 2, R 3 and R 5 are each independently H, R m , OH, OR m , SH, SR m , NH 2 , NHR m , NR m R m ' , NO 2 , Me 3 Sn And halo,
  • R m and R m ′ are as defined above;
  • R 4 is H, R m, OH, OR m, SH, SR m, NH 2, NHR m, NR m R m ', NO 2, Me 3 Sn, halo, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 1- 6 alkoxy, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 2- 6-alkynyl, substituted or unsubstituted C 3- 6 cycloalkyl, substituted or unsubstituted hwandoen 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 5- C 12 aryl, substituted or unsubstituted 5 to 7 membered heteroaryl, -CN, -NO 2, -NCO, -OR n, - OC (O) R n , -OC (O) NR n R n ' , -OS (O
  • C 1- 6 alkyl, C 1- 6 alkoxy, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 12 aryl, 5 to 7 membered each hydrogen atom of the heteroaryl are each independently a C 1 - 6 alkyl, C 1- 6 alkoxy, C 2 - 6 alkenyl, C 2- 6 alkynyl , C 3- C 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5 - 10 aryl, 5- to 7-membered heteroaryl group, -OR p, -OC
  • R n, R o, R p, and R q is independently H, C 1 - 7 alkyl, C 2 - 7 alkenylene, C 2- 7 alkynyl, C 3- 13 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10, selected from aryl, and a 5- to 7-membered group consisting of heteroaryl, and;
  • X and X ' are each independently -C (O) O *, -S (O) O *, -C (O) *, -C (O) NR *, -S (O) 2 NR *, -P Any one selected from the group consisting of (O) R'NR *, -S (O) NR *, and -PO 2 NR * is attached,
  • R, and R ' are each independently H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NHNH 2, halo, substituted or unsubstituted C 1- 8 alkyl, substituted or unsubstituted C 3- 8 cycloalkyl, substituted or unsubstituted C 1- 8 alkyl, substituted or unsubstituted C 1- 8 alkylthio, substituted or unsubstituted C 3- 20 heteroaryl, substituted or unsubstituted and 1- or di -C 8 alkylamino, - C 20 aryl or 5- mono-
  • Y and Y ' are each independently selected from the group consisting of O, S, and N (H);
  • R 6 is a substituted or unsubstituted saturated or unsaturated C 3-12 hydrocarbon chain
  • chain thereof may be interrupted by one or more heteroatoms, NMe or substituted or unsubstituted aromatic rings,
  • a chain or aromatic ring thereof has at least one position of hydrogen atom on its chain or aromatic ring, -NH, -NR m , -NHC (O) R m , -NHC (O) CH 2- [OCH 2 CH 2 ] n -R, or - May be unsubstituted or substituted with [CH 2 CH 2 O] n -R,
  • R m and R are the same as defined above for R m and R,
  • n is an integer from 1 to 12;
  • R 7 is H, substituted or unsubstituted C 1 - 6 alkyl, substituted or unsubstituted C 2 - 6 alkenyl, substituted or unsubstituted C 2- 6 alkynyl, substituted or unsubstituted C 3- 6 cycloalkyl alkyl, substituted or unsubstituted 3 to 7-membered optionally substituted heterocycloalkyl, unsubstituted or unsubstituted C 6 - 10 aryl, substituted or unsubstituted 5 to 7 membered heteroaryl, -OR r, -OC (O) r r , -OC (O) NR r R r ' , -OS (O) R r , -OS (O) 2 R r , -SR r , -S (O) R r , -S (O) 2 R r , -S (O) NR r R r '
  • C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10 aryl, 5 to 7-membered each hydrogen atom of the heteroaryl are each independently a C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, C 6 - 10 aryl, 5-7 membered heteroaryl, -OR t, -OC (O) R t, -OC (O
  • R r, R r ', R s, R s', R t, R t ', R u and R u' are each independently H, C 1- 7 alkyl, C 2-7 alkenyl, C 1-7 alkynyl, C 3- 13 is selected from cycloalkyl, 3 to 7-membered heterocycloalkyl, C 5-10 aryl, and 5- to 7-membered group consisting of-heteroaryl;
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and X are as defined above in Formula Ia,
  • R 8 is H, halo, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3- 6 heteroalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted C 5- 10 arylalkyl, substituted or unsubstituted 5 to 7 membered heteroaryl, -CN, -NO 2, - NCO, -OH, OR m , -OC (O) R m , -OC (O) NR m R m ', -OS (O) R m , -OS (O) 2 R m , -SR m , -S (O) R m , -S (O) 2 R m , -S (O) NR m R m '
  • C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 heteroalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, or a 5- to 7-membered when a heteroaryl group optionally substituted C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 heteroalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, or 5 to 7 membered each hydrogen atom of the heteroaryl are each independently C 1-6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 heteroalkyl, 3 to 7-membered heterocycloalkyl , 5- C 10 aryl, 5 to 7 membered heteroaryl, -OR m, -OC (O) R m, -OC (O) NR m R m ', -OS (O) R m,
  • R m , R m ' , R n and R n ' are as defined in Formula Ia,
  • Z a and Z b are each independently O, N, or S,
  • R 12a, R 13a, and R 14a are each independently selected from H, substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 2- 6 alkynyl, substituted or unsubstituted C 3- 6 cycloalkyl, substituted or unsubstituted 3 to 7 membered heterocycloalkyl, substituted or unsubstituted 5- C 10 aryl, substituted or unsubstituted 5 to 7 membered heteroaryl, -C (O) R 15a , -C (O) OR 15a and -C (O) NR 15a R 15a ' , wherein R 15a and R 15a' are as defined in R m ,
  • C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, 5 to 7 membered heteroaryl when the aryl is substituted each is hydrogen C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocyclyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, 5 to 7 membered heteroaryl, -OR o, -OC (O) R o, -OC (O) NR o R o ', -OS (O) R o, - OS (O) 2 R o , -SR o , -S (O) R o , -S (O) 2 R o , -S (O) NR o R o '
  • R 13a and R 14a combine with the atoms to which they are attached to form a 3 to 7-membered heterocyclyl, or 3 to 7-membered heterocycloalkyl, or R 13a and R 14a to which they are attached Can be combined together to form a 3 to 7 membered heteroaryl,
  • 3 to each of the hydrogen atoms present in the 7-membered heterocycloalkyl or 3 to 7-membered heteroaryl are each independently a C 1- 6 alkyl, C 2- 6 alkenyl, C 2- 6 alkynyl, C 3- 6 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, 5 to 7 membered heteroaryl, -OR o, -OC (o) R o, - OC (O) NR o R o ' , -OS (O) R o , -OS (O) 2 R o , -SR o , -S (O) R o , -S (O) 2 R o , -S (O) NR o R o ' , -S (O) 2 NR o R o ' , -OS (O) NR o R o R o , -OS (O) NR o
  • R n, R n ', R o, R o', R p, and R p ' are each independently H, C 1- 7 alkyl, 2- C 7 alkenyl, C 2- 7 alkynyl, C 3- 13 cycloalkyl, 3 to 7-membered heterocycloalkyl, 5- C 10 aryl, and a 5- to 7-membered heteroaryl is selected from the group consisting of;
  • R 1 ′ , R 2 ′ , R 3 ′ , R 4 ′ , R 5 ′ , R 7 ′, and R 8 ′ are R 1 , R 2 , R 3 , R 4, R 5 , It is as defined about R ⁇ 7> and R ⁇ 8> .
  • the dashed line indicates the presence of a double bond between C2 and C3.
  • R 1 is a substituted or unsubstituted C 1- 6 alkyl, substituted or unsubstituted C 2- 6 alkenyl, substituted or unsubstituted C 5-7 aryl, and substituted or unsubstituted C It is selected from the group consisting of 3-6 heteroaryl.
  • R 2 , R 3 and R 5 are each independently H or OH.
  • R 4 is C 1-6 alkoxy, more specifically methoxy, ethoxy or butoxy.
  • X and X ' are each independently selected from the group consisting of -C (O) O *, -C (O) * and -C (O) NR *,
  • R is each independently H, OH, N 3 , CN, NO 2 , SH, NH 2 , ONH 2 , NNH 2 , halo, substituted or unsubstituted C 1-8 alkyl or substituted or unsubstituted C 1- 8 alkoxy, in the case where C 1- 8 alkyl, C 1- 8 alkoxy which is substituted, H, OH, N 3, CN, NO 2, SH, NH 2, ONH 2, NNH is substituted by 2, or halo .
  • R 6 is a substituted or unsubstituted saturated or unsaturated C 3-8 hydrocarbon chain
  • Its chain may be interrupted by one or more heteroatoms or substituted or unsubstituted aromatic rings,
  • heteroatom is O, S or N (H)
  • aromatic ring is benzene, pyridine, imidazole or pyrazole,
  • At least one position of a hydrogen atom on the chain or aromatic ring is -NHC (O) CH 2- [OCH 2 CH 2 ] n -R, or -[CH 2 CH 2 O] n -R can be substituted,
  • n is an integer of 1-6.
  • pyrrolobenzodiazepine dimer precursor pharmaceutically acceptable salt or solvate thereof selected from:
  • R O and R ′ O are each an oxygen protecting group and may be the same as or different from each other.
  • the present invention also provides a conjugate having the structure of formula IIa or a pharmaceutically acceptable salt or solvate thereof:
  • Ligand is a ligand
  • L is a linker
  • D is a pyrrolobenzodiazepine dimer precursor as described above, wherein the linker is selected from the N10, N10 ', or N10 and N10' positions of D, or X, X 'or X and X' of D as described above.
  • n is an integer from 1 to 20.
  • the linker is bonded to D via the N10 and N10 'positions of D, or X and X' of D.
  • n is an integer from 1 to 10.
  • the present invention also provides a pyrrolobenzodiazepine dimer precursor-linker compound having the structure of Formula IIb or Formula IIb ', a pharmaceutically acceptable salt or solvate thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y, R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 7 ' , X ', Y', R 8 , Z a , Z b , R 12a , R 13a , R 14a , R 8 ', Z a ', Z b ', R 12a ', R 13a ', and R 14a ' are Each as defined in claim 2 for compounds of formula (Ia) and formula (Ia '),
  • each independently are Xa and Xa '(bond), or a substituted or unsubstituted C 1- 6 alkylene, and, if this is a C 1- 6 alkylene substituted with a hydrogen, C 1-8 alkyl or C 3 Substituted with -8 cycloalkyl,
  • G and G ' are glucuronide groups, galactoside groups or derivatives thereof,
  • Z is H, C 1- 8 alkyl, halo, NO 2, CN, , And-(CH 2 ) m -OCH 3 ,
  • R 8, R 9 and R 10 is selected from each independently H, C 1- 8 alkyl, C 2- 6 alkenyl, and the group consisting of C 1- 6 alkoxy, m is 0 to 12,
  • n is an integer of 1 to 3, when n is an integer of 2 or more, each Z may be the same or different from each other,
  • W is -C (O)-, -C (O) NR ''-, -C (O) O-, -S (O) 2 NR ''-, -P (O) R '''NR'' -, -S (O) NR '' -, or -PO 2 NR '' -, and wherein R '' and R '''are each independently H, C 1- 8 alkyl, C 3- 8 cycloalkyl, 1- C 8 alkoxy, C 1- 8 alkyl thio, mono- or di -C 1-8 alkylamino, C 3-20 heteroaryl, or C 6-20 aryl,
  • L is one or more units selected from the group consisting of a branching unit, a connection unit and a binding unit, or a combination of these units, wherein the connection unit is a combination of W, Connecting the W and the branching unit, the branching unit and the branching unit, or the branching unit and the coupling unit, wherein the branching unit connects the connection unit and the W, or the connection unit and another connection unit,
  • Branching unit 100 C 2- alkenyl (wherein the carbon atom of the alkenyl group is one or more N, O and may be substituted with a hetero atom selected from the group consisting of S, alkenyl has one or more C 1- 20 may be further substituted with alkyl), hydrophilic amino acid, -C (O)-, -C (O) NR '''-, -C (O) O-,-(CH 2 ) s- NHC (O)-(CH 2 ) t -,-(CH 2 ) u -C (O) NH- (CH 2 ) v -,-(CH 2 ) s -NHC (O)-(CH 2 ) t- C (O)-,-(CH 2 ) u -C (O) NH- (CH 2 ) v -C (O)-,-S (O) 2 NR '''-, -P (O) R ''''NR'
  • the connecting unit is-(CH 2 ) r (V (CH 2 ) p ) q- , where r is an integer from 0 to 10, p is an integer from 0 to 12, q is an integer from 1 to 20 and , V is a single bond, -O-, or S-,
  • L 1 is a single bond or a C 2- 30 alkenyl Al
  • R 11 is H or C 1-10 alkyl
  • L 2 is a C 2- 30 alkenyl group, and;
  • R v is -NH 2, N 3, substituted or unsubstituted C 1- 12 alkyl, C 1- 12 alkynylene, C 1- 3 alkoxy, substituted or unsubstituted C 3- 20 heteroaryl, C 3-20 ring Heterocyclyl or substituted or unsubstituted C 5-20 aryl,
  • Xa and Xa ' are each independently a bond or C 1-3 alkyl.
  • Z is H, , And-(CH 2 ) m -OCH 3 ,
  • W is -C (O)-, -C (O) NR '''-or -C (O) O-, wherein R''' is H or C 1-8 alkyl ,
  • L is one or more units selected from the group consisting of a branching unit, a connection unit and a binding unit, or a combination of these units, wherein the connection unit is a combination of W, Connecting the W and the branching unit, the branching unit and the branching unit, or the branching unit and the coupling unit, wherein the branching unit connects the connection unit and the W, or the connection unit and another connection unit,
  • Branching units C 2- 8 alkenyl (wherein the carbon atom of the alkenyl group is one or more N, O and may be substituted with a hetero atom selected from the group consisting of S, alkenyl has one or more C 1- 6 may be further substituted with alkyl), or a hydrophilic amino acid, -C (O)-, -C (O) NR '''-, -C (O) O-,-(CH 2 ) s -NHC (O)-(CH 2 ) t -,-(CH 2 ) u -C (O) NH- (CH 2 ) v -,-(CH 2 ) s -NHC (O)-(CH 2 ) t -C (O) -, or - (CH 2) u -C ( O) NH- (CH 2) v -C (O) - , and (wherein, R ''' is H, C 1- 8 alkyl, C 3- 8
  • the connecting unit is-(CH 2 ) r (V (CH 2 ) p ) q- , where r is an integer from 0 to 10, p is an integer from 0 to 12, q is an integer from 1 to 20 and , V is a single bond, or -O-,
  • L 1 is a single bond or a C 2- 8 alkenyl Al
  • R 11 is H or C 1- 6 alkyl
  • L 2 is C 2- 8 alkenyl
  • the connecting unit is-(CH 2 ) r (V (CH 2 ) p ) q- ,
  • r is an integer from 0 to 8
  • p is an integer from 1 to 12
  • q is an integer from 1 to 10
  • V is a single bond or -O-.
  • G and G ' may each independently be a ⁇ -glucuronide group, galactoside group or derivative thereof.
  • pyrrolobenzodiazepine dimer precursor-linker compound of Formula IIc a pharmaceutically acceptable salt or solvate thereof:
  • Dashed lines indicate any presence of a double bond between C1 and C2, or C2 and C3,
  • R 1 is methyl, ethyl, methylene, methoxy and substituted or doedoe selected from the group consisting of unsubstituted phenyl, when phenyl is substituted with H, OH, halo, C 1- 6 alkyl, C 1- 6 alkoxy and C 6 - is substituted with substituents selected from the group consisting of 12-aryl,
  • n 1 to 10
  • n is an integer from 1 to 10.
  • R 1 is methyl, methylene; And substituted with H, OH, halo, C 1- 6 substituents selected from the group consisting of alkyl and C 1- 6 alkoxy or may be an unsubstituted phenyl.
  • m may be an integer of 2 to 8, specifically an integer of 3 to 7, more specifically an integer of 4 to 6.
  • n may be an integer of 2 to 8, specifically an integer of 3 to 7, more specifically an integer of 4 to 6.
  • the present invention also provides a pyrrolobenzodiazepine dimer precursor-linker compound, a pharmaceutically acceptable salt or solvate thereof, having the following chemical structure.
  • a pyrrolobenzodiazepine dimer precursor-linker compound having the following chemical structure.
  • the following pyrrolobenzodiazepine dimer precursor-linker compounds are illustrative, and one of ordinary skill in the art can make and use various pyrrolobenzodiazepine dimer-linker compounds within the scope described above:
  • the present invention also provides a pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate having the structure of Formula IIIa or IIIb, a pharmaceutically acceptable salt or solvate thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y, R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 7 ' , X ', Y', R 8 , Z a , Z b , R 12a , R 13a , R 14a , R 8 ', Z a ', Z b ', R 12a ', R 13a ', and R 14a ' are Each as defined in claim 2 for compounds of formula (Ia) and formula (Ia '),
  • Xa, G, Z, W, L, Xa ', G', Z ' are the same as defined for the compound of formula IIb in claim 11, respectively;
  • Ligand is an antigen binding moiety.
  • Ligand is a protein
  • the protein is an oligopeptide, polypeptide, antibody, fragment of an antigenic polypeptide, or a phosphor.
  • the protein has one or more amino acid motifs that can be recognized by isoprenoid transferases. That is, the C-terminus (fragment, analog or derivative thereof) of a protein can be bound to an amino acid motif that can be recognized by an isoprenoid transferase.
  • the protein and the amino acid motif may further comprise a spacer unit consisting of an amino acid, oligopeptide or polypeptide.
  • the protein is covalently linked to the linker via an amino acid motif.
  • the amino acid motif may be covalently bonded to the C-terminus of the protein, or covalently bonded to at least one spacer unit covalently to the C-terminus of the protein.
  • a protein may be directly covalently linked to an amino acid motif or covalently linked to a spacer unit to be linked to an amino acid motif.
  • the amino acid spacer unit is composed of 1 to 20 amino acids, of which a glycine unit is preferable.
  • the C-terminus of the protein is that of the light or heavy chain of the antibody.
  • the protein is a monoclonal antibody.
  • the isoprenoid transferase comprises a farnesyl protein transferase (FTase) or a geranylgeranyl transferase (GGTase), which are the C-terminal cysteines of the target protein of the farnesyl or geranyl-geranyl residues, respectively. Involves transition to (s). GGTase can be classified into GGTase I and GGTase II. FTase and GGTase I can recognize CAAX motifs.
  • FTase and GGTase I can recognize CAAX motifs.
  • the amino acid motif is CYYX, XXCC, XCXC or CXX, wherein C is cysteine, Y is an aliphatic amino acid, and X is an amino acid that determines the substrate specificity of the isoprenoid transferase.
  • the protein having the amino acid motif is A-HC- (G) Z CVIM, A-HC- (G) zCVLL, A-LC- (G) Z CVIM and A-LC- (G ) Z CVLL, wherein A represents an antibody, HC represents a heavy chain, LC represents a light chain, G represents a glycine unit and z is an integer from 0 to 20.
  • Isoprenoid transferases can recognize substrates as well as isosubstrates.
  • Iso substrates refer to substrate analogs with modifications to the substrate.
  • Isoprenoid transferases alkylate specific amino acid motifs (eg, CAAX motifs) at the C-terminus of the protein (see Benjamin P. Duckworth et al, ChemBioChem 2007, 8, 98; Uyen TT Nguyen et al, ChemBioChem 2007, 8, 408; Guillermo R. Labadie et al, J. Org.Chem. 2007, 72 (24), 9291; James W. Wollack et al, Chem BioChem 2009, 10, 2934).
  • Functionalized proteins can be produced using isoprenoid transferases and iso substrates via alkylation in the C-terminal cysteine (s).
  • cysteine residues of the C-terminal CAAX motif can be reacted with iso substrates using isoprenoid transferases.
  • AAX can then be removed by proteases.
  • the obtained cysteine can then be methylated at the carboxy terminus by enzyme (Iran M. Bell, J. Med. Chem. 2004, 47 (8), 1869).
  • Proteins of the present invention can be prepared using any molecular or cellular biology well known in the art. For example, transient transfection may be used. Genetic sequences encoding specific amino acid motifs that can be recognized by isoprenoid transferases are known phrases using standard PCR techniques to express a protein (fragment or analog thereof) having a specific amino acid motif at its C-terminus. Can be inserted into the mid vector. As such, proteins having one or more amino acid motifs that can be recognized by isoprenoid transferases can be expressed.
  • the protein is a monoclonal antibody
  • at least one light chain of the monoclonal antibody, at least one heavy chain of the monoclonal antibody, or both has an amino acid site having an amino acid motif that can be recognized by an isoprenoid transferase It may include, and those skilled in the art can immediately select a protein (eg target cells of the subject) to selectively bind the target of interest.
  • it may comprise a fragment of an antibody or antigen that specifically binds to a target of interest.
  • the amino acid motif is CYYX, XXCC, XCXC or CXX (wherein C is cysteine, Y is aliphatic amino acid and X is amino acid that determines the substrate specificity of isoprenoid transferase), More preferably, the amino acid motif is CYYX.
  • the present invention also provides a pharmaceutical composition for preventing or treating a proliferative disease, comprising the pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate, pharmaceutically acceptable salts or solvates thereof described above.
  • the present invention also relates to pyrrolobenzodiazepine dimer precursor-linker-ligand conjugates, pharmaceutically acceptable salts or solvates thereof; And it provides a pharmaceutical composition for the prevention or treatment of proliferative disease, comprising a pharmaceutically acceptable excipient.
  • the present invention also relates to pyrrolobenzodiazepine dimer precursor-linker-ligand conjugates, pharmaceutically acceptable salts or solvates thereof; One or more therapeutic co-agents; And it provides a pharmaceutical composition for the prevention or treatment of proliferative disease, comprising a pharmaceutically acceptable excipient.
  • the therapeutic co-agent is an agent that exhibits a prophylactic, ameliorating or therapeutic effect on a proliferative disease, or an agent that can reduce the onset of side effects that occur when administering a proliferative disease treatment, or enhances immunity.
  • Agents which may be effective, and the like, but are not limited thereto, and have a therapeutically useful effect when applied in the form of a combination with pyrrolobenzodiazepines, and / or further improve the stability of pyrrolobenzodiazepines, and / or This means that any agent that can reduce the side effects that may occur when benzodiazepines are administered and / or enhance the immunity to maximize the therapeutic effect may be applied in any combination.
  • the proliferative disease refers to a cell proliferation related disease in which undesirably excessive or abnormal cells, such as neoplasia or hyperplastic growth, are undesirably controlled in vitro or in vivo.
  • Proliferative diseases can be selected from the group consisting of neoplasms, tumors, cancers, leukemias, psoriasis, bone diseases, fibrotic disorders, and atherosclerosis. Examples of neoplasms and tumors include histiocytoma, glioma, astrocytoma, osteoma and the like.
  • the cancer is lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma And melanoma may be selected from the group, but if the pyrolobenzodiazepine is a carcinoma that can exhibit a therapeutic effect is applicable to all.
  • the invention also has a proliferative disease, comprising administering to a subject an effective amount of a pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate, a pharmaceutically acceptable salt or solvate thereof, for treating a proliferative disease.
  • a proliferative disease comprising administering to a subject an effective amount of a pyrrolobenzodiazepine dimer precursor-linker-ligand conjugate, a pharmaceutically acceptable salt or solvate thereof, for treating a proliferative disease.
  • a method of treating cancer comprising administering the pharmaceutical composition to a patient.
  • the present invention is suitable for use in providing a PBD compound at a target position in a subject.
  • the conjugate according to the invention releases an active PBD compound which has no linker moiety, and there is nothing that can affect the reactivity of the PBD compound.
  • conjugates refers to cell binders that are covalently bound to one or more molecules of a cytotoxic compound.
  • a “cell binding agent” is a molecule having affinity for a biological target, and may be, for example, a ligand, a protein, an antibody, specifically a monoclonal antibody, a protein or antibody fragment, peptide, oligonucleotide, oligosaccharide, The binder serves to induce the biologically active compound to the biological target.
  • the conjugate can be designed to target tumor cells via cell surface antigens.
  • the antigen may be a cell surface antigen that is overexpressed or expressed in an abnormal cell type.
  • the target antigen may be one expressed only on proliferative cells (eg tumor cells). Target antigens can usually be selected based on different expressions between proliferative and normal tissues.
  • the ligand is bound to the linker.
  • an “antibody” herein is an immunoglobulin molecule capable of specifically binding to a target such as carbohydrates, polynucleotides, lipids, polypeptides, and the like through at least one antigen recognition site located in the variable region of an immunoglobulin molecule.
  • antibody refers to an intact polyclonal or monoclonal antibody, as well as any antigen binding portion of an intact antibody that possesses the ability to specifically bind a given antigen (eg, "Antigen-binding fragment") or a single chain thereof, a fusion protein comprising an antibody, and any other modified arrangement of an immunoglobulin molecule comprising an antigen recognition site, such as, but not limited to, Fab; Fab '; F (ab ') 2 Fd fragments; Fv fragments; Single domain antibody (dAb) fragments; Isolated complementarity determining regions (CDRs); Encompasses single chain (scFv) and single domain antibodies (e.g., shark and camel antibodies), maxibody, minibody, intrabody, diabody, tribody, tetrabody, v-NAR and bis-scFv ( See, eg, Hollinger and Hudson, 2005, Nature Biotechnology 23 (9): 1126-1136).
  • Antibodies include any class of antibody, such as IgG, IgA or IgM (or a subclass thereof), and the antibody need not be in any particular class.
  • immunoglobulins can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, some of which are additionally in subclasses (isotypes) such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. Can be classified.
  • the heavy chain (HC) constant domains corresponding to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma and mu, respectively.
  • Subunit structures and three-dimensional coordination of different classes of immunoglobulins are well known.
  • Antibodies of the invention can be prepared using techniques well known in the art, such as recombinant techniques, phage display techniques, synthetic techniques, or combinations of these techniques, or other techniques that are readily known in the art.
  • an “isolated antibody” refers to an antibody that is substantially free of other antibodies with different antigen specificity and may be substantially free of other cellular materials and / or chemicals.
  • biological target refers to an antigen located on the surface of a tumor, cancer cell, or extracellular matrix.
  • linker refers to a compound that covalently binds a cytotoxic compound to a ligand.
  • the linker disclosed in PCT / US2016 / 063564 and PCT / US2016 / 063595 can be used.
  • a “therapeutic agent” herein is an agent that exerts cytotoxic, cytostatic and / or immunomodulatory effects on proliferative diseases, such as cancer cells or activated immune cells.
  • therapeutic agents include cytotoxic agents, chemotherapeutic agents, cytostatic agents and immunomodulators.
  • chemotherapeutic agent is a chemical compound useful for the treatment of cancer.
  • a “subject” is intended to include humans and non-human animals, especially mammals.
  • subjects include human subjects, such as the concept comprising a human patient or a normal subject having a disorder described herein, more specifically cancer.
  • “Non-human animals” are useful for all vertebrates, eg, non-mammals (eg, chickens, amphibians, reptiles) and mammals, eg, non-human primates, livestock, and / or agriculture. Animals (eg, sheep, dogs, cats, cattle, pigs, etc.) and rodents (eg, mice, rats, hamsters, guinea pigs, etc.).
  • the subject is a human patient.
  • treatment refers to both therapeutic treatment and prophylactic or prophylactic measures.
  • Subjects in need of treatment include those already with the disease and subjects susceptible to the disease or subjects to which the disease is to be prevented.
  • the term when used with respect to a subject in need of a disease or treatment, the term includes, compared to untreated subjects, slowing or slowing disease progression, preventing symptoms, reducing disease and / or symptom severity, or reducing disease duration. It is not limited to one.
  • administering refers to providing and / or contacting and / or delivering a compound or compounds by any suitable route to achieve the desired effect.
  • Administration may be oral, sublingual, parenteral (eg, intravenous, subcutaneous, intradermal, intramuscular, intraarticular, intraarterial, intravitreal, intrasternal, intrathecal, intralesional or intracranial injection), transdermal, topical, Buccal, rectal, vaginal, nasal, ophthalmic, inhalation and administration via implants may include, but is not limited to.
  • unsubstituted or substituted refers to a parent group which may be unsubstituted or substituted
  • substituted refers to a parent group having one or more substituents
  • substituted refers to a mosquito refers to a chemical moiety covalently bonded to a parent group or fused to a parent group.
  • Halo refers to fluorine, chlorine, bromine, iodine and the like.
  • alkyl is a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an aliphatic or cycloaliphatic, saturated or unsaturated (unsaturated, fully unsaturated) hydrocarbon compound
  • saturated alkyl examples are methyl, ethyl, propyl, butyl
  • saturated linear alkyl examples include pentyl, hexyl, heptyl and the like, and examples of saturated branched alkyl such as methyl, ethyl, n-propyl, n-butyl, n-pentyl (amyl), n-hexyl and n-heptyl Isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl and the like.
  • alkoxy means -OR [where R is an alkyl group], for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy etc. are mentioned.
  • aryl means a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound having a ring atom.
  • alkenyl is an alkyl having at least one carbon-carbon double bond.
  • alkynyl is an alkyl group having at least one carbon-carbon triple bond, and examples of the unsaturated alkynyl group include ethynyl and 2-propynyl.
  • aryl relates to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound.
  • C 5- 7 aryl as a moiety having from 5 to 7 ring atoms, and 1 is obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound means a moiety
  • C 5 - 10 aryl means that the moiety has 5 to 10 ring atoms, and is a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound.
  • C 5-7 , C 5-10, etc. refers to the range of the number of ring atoms or the number of ring atoms, whether they are carbon atoms or hetero atoms.
  • C 5- 6 aryl relates to an aryl group having 5 or 6 ring atoms.
  • the ring atoms may all be carbon atoms as in the "carboaryl group".
  • Examples of carboaryl groups include, but are not limited to, those derived from benzene, naphthalene, azulene, anthracene, phenanthrene, naphthacene and pyrene.
  • aryl groups including fused rings wherein at least one is an aromatic ring include, but are not limited to, groups derived from indane, indene, isoindene, tetralin, acenaphthene, fluorene, penalene, acefenanthrene and aceanthrene It is not limited.
  • the ring atom may comprise one or more hetero atoms as in a "heteroaryl group".
  • heteroaryl is an aryl containing one or more hetero atoms, for example pyridine, pyrimidine, benzothiophene, furyl, dioxalanyl, pyrrolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidy More specifically, benzofuran, isobenzofuran, indole, isoindole, indolizine, indolin, isoindolin, purine (adenine or guanine), benzimidazole, indazole, benzoxazole, benzisoxazole, C 9 , chrome, isochromen, chromman, isochrome, benzo with two fused rings derived from benzodioxol, benzofuran, benzotriazole, benzothiofuran, benzothiazole, benzothiadiazole Two fused rings derived from dioxane, quinoline
  • cycloalkyl is an alkyl group which is a cyclyl group and relates to a monovalent portion obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon compound.
  • cycloalkyl groups include, but are not limited to, those derived from:
  • Saturated monocyclic hydrocarbon compounds cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane and methylcyclohexane;
  • Unsaturated monocyclic hydrocarbon compounds cyclopropene, cyclobutene, cyclopentene, cyclohexene, methylcyclopropene, dimethylcyclopropene, methylcyclobutene, dimethylcyclobutene, methylcyclopentene, dimethylcyclopentene and methylcyclohexene;
  • Saturated heterocyclic hydrocarbon compounds norcaran, norpinan, norbornane.
  • heterocyclyl relates to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound.
  • Prefixes eg, C 1-12 , C 3-8, etc.
  • C 3- 6 heterocyclyl relates heterocyclyl groups having from 3 to 6 ring atoms.
  • monocyclic heterocyclyl groups include, but are not limited to, those derived from:
  • N 1 aziridine, azetidine, pyrrolidine, pyrroline, 2H- or 3H-pyrrole, piperidine, dihydropyridine, tetrahydropyridine, azepine;
  • N 2 imidazolidine, pyrazolidine, imidazoline, pyrazoline, piperazine;
  • O 1 oxirane, oxetane, oxolane, oxol, oxane, dihydropyran, pyran, oxepin;
  • O 2 dioxolane, dioxane and dioxepane
  • N 1 O 1 tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, oxazine
  • N 1 S 1 thiazolin, thiazolidine, thiomorpholine;
  • N 1 O 1 S 1 Oxathiazine.
  • a "prodrug” refers to pyrrolobenzodia by the action of an enzyme, gastric acid under in vivo physiological conditions (e.g., enzymatic oxidation, reduction and / or hydrolysis). It refers to a compound that can be converted directly or indirectly to zepin drugs.
  • an acid addition salt formed by a pharmaceutically acceptable free acid may be used, and an organic acid or an inorganic acid may be used as the free acid.
  • the organic acid is not limited thereto, but citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, Glutamic acid and aspartic acid.
  • the inorganic acid also includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.
  • the salt may be formed with a suitable cation.
  • suitable inorganic cations include alkali metal ions such as Na + and K +, alkaline earth cations such as Ca 2 + and Mg 2 +, and other cations such as Al + 3, but is not limited to this.
  • suitable organic cations include, but are not limited to, ammonium ions (ie, NH 4 + ) and substituted ammonium ions (eg, NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • substituted ammonium ions examples include those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine , Phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine.
  • An example of a typical quaternary ammonium ion is N (CH 3 ) 4 + .
  • a compound When a compound has functional groups which may be a cation or cations, or may form a salt (e.g., -NH 2 may be that one -NH 3 +), suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid and phosphorous acid, and the like.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-aceticoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethane Disulfonic acid, ethanesulfonic acid, fumaric acid, glutenic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalene carboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, Malic acid, methanesulfonic acid, slime acid, oleic acid, oxalic acid, palmitic acid, palmic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid,
  • solvate refers to a molecular complex between a compound according to the invention and a solvent molecule
  • examples of solvates are water, isopropanol, ethanol, methanol, dimethylsulfoxide (dimethylsulfoxide), ethyl acetate, acetic acid, ethanolamine, or a compound according to the present invention in combination with a solvent thereof, but is not limited thereto.
  • solvates may conveniently be referred to as hydrates such as monohydrate, dihydrate, trihydrate and the like.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers can include macromolecules that are typically slowly metabolized, such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers, lipid aggregates, and the like. Acceptable carriers may be appropriately selected and used by those skilled in the art.
  • composition comprising a pharmaceutically acceptable carrier may be in various oral or parenteral formulations.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. Mix is prepared. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like can also be used.
  • Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the pharmaceutical composition is selected from the group consisting of injections, tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories. It can have any one formulation.
  • the active ingredient may be in the form of an acceptable aqueous solution for parenteral administration with pyrogen-free and suitable pH, isotonicity and stability.
  • suitable solutions using, for example, isotonic vehicles, such as aqueous sodium chloride solution, Ringer's solution, lactate Ringer's solution, and the like, and can be included as necessary as preservatives, stabilizers, buffers, antioxidants or other additives.
  • Solid forms suitable for injection can also be prepared as emulsions or in the form of polypeptides encapsulated in liposomes.
  • the phrase “effective amount” or “therapeutically effective amount” refers to the amount necessary (relative to dosage and administration period and means) to achieve the desired therapeutic result.
  • An effective amount is at least the minimum amount of active agent necessary to confer a therapeutic benefit to a subject and is below the toxic amount.
  • the dosage can be administered in the range of about 100 ng to about 100 mg / kg per patient, more typically in the range of about 1 ⁇ g / kg to about 10 mg / kg.
  • the active compound is a salt, ester, amide, prodrug, or the like, the dosage is calculated based on the parent compound, so the actual weight used is increased proportionally.
  • the pyrrolobenzodiazepine compound according to the present invention may be formulated to include, but is not limited to, 0.1 mg to 3000 mg, 1 mg to 2000 mg, 10 mg to 1000 mg of active ingredient per dosage form.
  • the active ingredient may be administered to obtain a peak plasma concentration of the active compound of about 0.05 ⁇ M to 100 ⁇ M, 1 ⁇ M to 50 ⁇ M, 5 ⁇ M to 30 ⁇ M.
  • a peak plasma concentration of the active compound of about 0.05 ⁇ M to 100 ⁇ M, 1 ⁇ M to 50 ⁇ M, 5 ⁇ M to 30 ⁇ M.
  • a peak plasma concentration of the active compound of about 0.05 ⁇ M to 100 ⁇ M, 1 ⁇ M to 50 ⁇ M, 5 ⁇ M to 30 ⁇ M.
  • the concentration of the active compound in the pharmaceutical composition can be determined by the rate of absorption, inactivation and excretion of the drug and other factors known to those skilled in the art. Dosage may vary depending on the severity of the condition / disease. In addition, the dosage and dosing regimen for a particular patient may be adjusted according to the occupational supervisor's professional judgment, taking into account the degree, necessity, age, responsiveness to the drug, etc. of the patient's symptoms / diseases. The scope is merely one example and is not intended to limit the embodiments of the claimed compositions thereto.
  • the active ingredient may also be administered once, or several smaller doses may be administered.
  • the precursor compounds, or precursor-linker compounds, precursor-linker-ligand conjugate compounds according to the invention can be used to treat proliferative diseases, in particular cancer diseases.
  • proliferative disease refers to unwanted or uncontrolled cell proliferation of undesirable excessive or abnormal cells, such as neoplasia or hyperplasia, in vitro or in vivo.
  • Proliferative diseases include, for example, neoplasia, tumors, cancer, leukemia, psoriasis, bone diseases, fibrotic disorders, atherosclerosis, and the like, and may include, but are not limited to, benign, premalignant or malignant cell proliferation. .
  • the cancer may be lung cancer, small cell lung cancer, gastrointestinal cancer, colon cancer, bowel cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma or melanoma It is not limited.
  • the pyrrolobenzodiazepine precursor, pyrrolobenzodiazepine precursor-linker compound, and pyrrolobenzodiazepine-linker-ligand conjugate according to the invention can be synthesized according to the following procedure.
  • Pyrrolobenzodiazepine precursor-linker compounds, and pyrrolobenzodiazepine precursor-linker-ligand conjugates according to the present invention can be prepared using the knowledge of those skilled in the art using the techniques provided herein.
  • the pyrrolobenzodiazepine dimer precursor (prodrug), pyrrolobenzodiazepine dimer precursor (prodrug) -linker, or pyrrolobenzodiazepine dimer precursor (prodrug) -linker-ligand conjugate according to the present invention the stability of the compound itself and in the plasma It is excellent in stability and has an advantage in terms of toxic expression, and is industrially useful in that it is possible to target a proliferative disease such as cancer, specific treatment, maximization of drug efficacy and minimization of side effects.
  • Oxalyl chloride (3.1 mL, 36.2 mmol) was dissolved in dichloromethane (40 mL) and then dimethyl sulfoxide (4.7 mL, 66.4 mmol) was added at -78 ° C under nitrogen atmosphere. After 10 minutes, compound 1 (10 g, 30.2 mmol, Compound 1 J. Org. Chem., 2003, 68, was prepared by a method described in the 3923-3931) to a solution in dichloromethane (140 mL) Slowly added, the reaction solution was stirred for 1 hour, triethylamine (16.7 mL, 120.6 mmol) was added thereto, and the reaction temperature was slowly raised to 0 ° C. for 2 hours.
  • reaction solution was diluted with dichloromethane (200 mL) and the organic layer was washed with saturated aqueous ammonium chloride solution (200 mL) and brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 2 (9.5 g, 95%).
  • reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with brine (50 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure and purification by column chromatography yielded compound 23 (2.5 g, 72%).
  • reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure and purification by column chromatography yielded compound 25 (800 mg, 40%).
  • Compound 32 was prepared in a similar manner to the synthesis of Compound 22 from Compound 19 and Compound 31 (Compound 31 was prepared by the method described in PCT / US2016 / 063564).
  • EI-MS m / z: [M + H] + 731.5.
  • reaction solution was concentrated, diluted with dichloromethane (30 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 56 (1.15 mg, 54%) was obtained.
  • reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 58 (650 mg, 64%) was obtained.
  • Compound 85 was prepared by a method analogous to the synthesis of compound 28 from compound 9, compound 84 (compound 84 was prepared by the method described in WO2011 / 130598 A1), and compound 32.
  • reaction solution was concentrated, diluted with dichloromethane (30 mL), washed with brine (20 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure and purification by column chromatography gave compound 95 (130 mg, 43%).
  • reaction solution was concentrated, diluted with dichloromethane (50 mL), washed with brine (30 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure were followed by purification by column chromatography to give compound 97 (168 mg, 41%).
  • 1,3-Diaminopropane (0.93 mL, 11.1 mmol) was dissolved in dichloromethane (30 mL) and di- t -butyl dicarbonate (0.84 mL, 3.7 mmol) was added at 0 ° C. under nitrogen atmosphere. After stirring for 3 hours at room temperature, brine (50 mL) was added to the reaction solution, extracted with ethyl acetate (2 x 100 mL), and dried over anhydrous sodium sulfate. After filtration the reaction solution was concentrated under reduced pressure and purified by column chromatography to give compound 101 (658 mg, based on 100% Boc 2 O).
  • reaction solution was diluted with ethyl acetate (30 mL), washed with brine (20 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 132 (1.0 g, 83%) was obtained.
  • Compound 136 was prepared by a method analogous to the synthesis of compound 134 from compound 126 and compound 118. EI-MS m / z: [M + H] + 2032.98, 1/2 [M + H] + 1017.03.
  • Compound 138 was prepared by a method similar to the synthesis of compound 137 from compound 126 and compound 124. EI-MS m / z: [M + H] + 1647.60, 1/2 [M + H] + 824.31.
  • reaction solution was concentrated and diluted with ethyl acetate (100 mL), then saturated aqueous sodium hydrogen carbonate solution (100 mL) was added to the reaction solution, and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 ⁇ 100 mL) and dried over anhydrous sodium sulfate. Filtration, concentration and purification by column chromatography Compound 140 (1.53 g, 72%) was obtained.
  • reaction solution was concentrated and diluted with dichloromethane (50 mL), washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 143 (340 mg, 71%) was obtained.
  • reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with brine (2 x 50 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 145 (250 mg, 43%) was obtained.
  • reaction solution was concentrated, diluted with dichloromethane (100 mL), washed with brine (2 x 50 mL), and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, followed by purification by column chromatography Compound 147 (170 mg, 42%) was obtained.
  • Oxalyl chloride (2.1 mL, 14.1 mmol) was dissolved in dichloromethane (20 mL) and then dimethyl sulfoxide (1.5 mL, 21.1 mmol) was added at ⁇ 78 ° C. under nitrogen atmosphere. After 1 h, a solution of compound 158 (2.7 g, 6.9 mmol) in dichloromethane (50 mL) was added slowly. The reaction solution was stirred for 2 hours and then triethylamine (3.4 mL, 42.3 mmol) was diluted in dichloromethane (30 mL) and added slowly. The reaction temperature was slowly raised to 0 ° C. for 2 hours.
  • reaction solution was diluted with dichloromethane (100 mL) and the organic layer was washed with saturated aqueous ammonium chloride solution (200 mL) and brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, concentration and purification by column chromatography gave compound 159 (2.7 g, 96%).

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Abstract

La présente invention concerne un précurseur de pyrrolobenzodiazépine et un composé conjugué ligand-lieur de celui-ci, une composition le contenant, et en particulier, une utilisation thérapeutique de celui-ci en tant qu'agent anticancéreux. La présente invention est appropriée pour une utilisation sur le plan industriel et elle est caractérisée par la possibilité de cibler des maladies prolifératives telles que le cancer, d'effectuer un traitement spécifique, de maximiser les effets médicinaux, et de minimiser l'apparition d'effets secondaires. Le composé de l'invention est très stable, possède une excellente stabilité dans le plasma, et présente des avantages en termes de manifestation de toxicité.
PCT/KR2018/003744 2017-03-29 2018-03-29 Précurseur dimère de pyrrolobenzodiazépine et composé conjugué ligand-lieur associé Ceased WO2018182341A1 (fr)

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AU2018246806A AU2018246806B2 (en) 2017-03-29 2018-03-29 Pyrrolobenzodiazepine dimer precursor and ligand-linker conjugate compound thereof
NZ757701A NZ757701B2 (en) 2018-03-29 Pyrrolobenzodiazepine dimer precursor and ligand-linker conjugate compound thereof
CA3058360A CA3058360A1 (fr) 2017-03-29 2018-03-29 Promedicament de dimere de pyrrolobenzodiazepine et son compose de conjugue ligand-lieur
BR112019020136-0A BR112019020136B1 (pt) 2017-03-29 2018-03-29 Conjugado de profármaco de dímero de pirrolobenzodiazepina, composição farmacêutica compreendendo o mesmo e uso terapêutico do mesmo
MX2019011655A MX2019011655A (es) 2017-03-29 2018-03-29 Profarmaco de dimero de pirrolobenzodiazepina y compuesto conjugado ligando-conector de este.
IL269535A IL269535B2 (en) 2017-03-29 2018-03-29 Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same
CN201880003365.6A CN109790171B (zh) 2017-03-29 2018-03-29 吡咯并苯并二氮杂二聚物前体及其配体-连接体缀合化合物
EP18774896.7A EP3604311A4 (fr) 2017-03-29 2018-03-29 Précurseur dimère de pyrrolobenzodiazépine et composé conjugué ligand-lieur associé
JP2019515212A JP7664680B2 (ja) 2017-03-29 2018-03-29 ピロロベンゾジアゼピン二量体前駆体及びそのリガンド－リンカーコンジュゲート化合物
US16/328,256 US11654197B2 (en) 2017-03-29 2018-03-29 Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same
US18/113,948 US12398124B2 (en) 2017-03-29 2023-02-24 Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same
JP2023081396A JP2023113699A (ja) 2017-03-29 2023-05-17 ピロロベンゾジアゼピン二量体前駆体及びそのリガンド－リンカーコンジュゲート化合物

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CN112135638A (zh) * 2019-03-06 2020-12-25 乐高化学生物科学股份有限公司 包含抗人dlk1抗体的抗体-药物偶联物及其用途
CN113260621A (zh) * 2019-01-03 2021-08-13 乐高化学生物科学股份有限公司 安全性得到提高的吡咯并苯并二氮杂二聚体化合物及其用途
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JP2022530482A (ja) * 2019-05-02 2022-06-29 レゴケム バイオサイエンシズ， インク． トリス構造を有するリンカーを含むリガンド―薬物複合体
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US11975076B2 (en) 2015-11-25 2024-05-07 Legochem Biosciences, Inc. Antibody-drug conjugates comprising branched linkers and methods related thereto
US12398124B2 (en) 2017-03-29 2025-08-26 Ligachem Biosciences Inc. Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same
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WO2019166615A1 (fr) * 2018-03-01 2019-09-06 Medimmune Limited Procédés
US11524969B2 (en) 2018-04-12 2022-12-13 Medimmune Limited Pyrrolobenzodiazepines and conjugates thereof as antitumour agents
US11827703B2 (en) 2018-05-09 2023-11-28 Legochem Biosciences, Inc. Compositions and methods related to anti-CD19 antibody drug conjugates
JP2022516911A (ja) * 2019-01-03 2022-03-03 レゴケム バイオサイエンシズ， インク． 安定性が向上したピロロベンゾジアゼピン二量体化合物及びその用途
CN113260621A (zh) * 2019-01-03 2021-08-13 乐高化学生物科学股份有限公司 安全性得到提高的吡咯并苯并二氮杂二聚体化合物及其用途
EP3907226A4 (fr) * 2019-01-03 2022-09-07 LegoChem Biosciences, Inc. Composé dimère de pyrrolobenzodiazépine présentant une sécurité améliorée et son utilisation
JP7542266B2 (ja) 2019-01-03 2024-08-30 リガケム バイオサイエンシズ， インク． 安定性が向上したピロロベンゾジアゼピン二量体化合物及びその用途
CN109535035A (zh) * 2019-01-08 2019-03-29 吉尔生化（上海）有限公司 一种n-苄氧羰基-3-氨基-丙氨酸叔丁酯的制备方法
EP3936150A4 (fr) * 2019-03-06 2023-03-29 LegoChem Biosciences, Inc. Conjugués anticorps-médicament comprenant un anticorps contre dlk1 humain et utilisation associée
JP7664045B2 (ja) 2019-03-06 2025-04-17 リガケム バイオサイエンシズ， インク． ヒトｄｌｋ１に対する抗体を含む抗体薬物コンジュゲート及びその使用
CN112135638A (zh) * 2019-03-06 2020-12-25 乐高化学生物科学股份有限公司 包含抗人dlk1抗体的抗体-药物偶联物及其用途
US12209099B2 (en) 2019-03-15 2025-01-28 Medimmune Limited Azetidobenzodiazepine dimers and conjugates comprising them for use in the treatment of cancer
JP2022530482A (ja) * 2019-05-02 2022-06-29 レゴケム バイオサイエンシズ， インク． トリス構造を有するリンカーを含むリガンド―薬物複合体
WO2022015656A1 (fr) 2020-07-13 2022-01-20 Regeneron Pharmaceuticals, Inc. Analogues de camptothécine conjugués à un résidu de glutamine dans une protéine et leur utilisation
WO2022187591A1 (fr) 2021-03-05 2022-09-09 Go Therapeutics, Inc. Anticorps anti-glyco-cd44 et leurs utilisations
WO2023014863A1 (fr) 2021-08-05 2023-02-09 Go Therapeutics, Inc. Anticorps anti-glyco-muc4 et leurs utilisations
WO2023166322A1 (fr) 2022-03-04 2023-09-07 Iksuda Therapeutics Limited Conjugué d'anticorps anti-canag
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