EP3368091A1 - Bifunktionale prodrugs - Google Patents

Bifunktionale prodrugs

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Publication number
EP3368091A1
EP3368091A1 EP16790323.6A EP16790323A EP3368091A1 EP 3368091 A1 EP3368091 A1 EP 3368091A1 EP 16790323 A EP16790323 A EP 16790323A EP 3368091 A1 EP3368091 A1 EP 3368091A1
Authority
EP
European Patent Office
Prior art keywords
group
antibody
alkyl
optionally substituted
alkyl group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP16790323.6A
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German (de)
English (en)
French (fr)
Inventor
Lutz F. Tietze
Kamala PENCHALAIAH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Georg August Universitaet Goettingen
Original Assignee
Georg August Universitaet Goettingen
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Filing date
Publication date
Application filed by Georg August Universitaet Goettingen filed Critical Georg August Universitaet Goettingen
Publication of EP3368091A1 publication Critical patent/EP3368091A1/de
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • 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
    • 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
    • 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
    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
    • A61K47/6899—Antibody-Directed Enzyme Prodrug Therapy [ADEPT]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

  • the present invention is directed to novel compounds, more particularly to novel bifunctional prodrugs and drugs.
  • the present invention is directed to antibody-compound conjugates wherein the compound is a compound of the invention and to pharmaceutical compositions containing the compound or the antibody-compound conjugate.
  • chemotherapeutic agents are distributed throughout the body through the bloodstream so that they can reach all cells. Chemotherapeutic agents have cytostatic effects on human cells, that is, they prevent cell proliferation, or they are cytotoxic, that is, they cause the cells to die.
  • cytostatics show their mechanism of action in proliferating cells and tumor cells are among the rapidly proliferating cell types, they are used as chemotherapeutic agents.
  • the non-tumor cells of the treated person are also affected, especially those of the bone marrow, the hair roots or mucosal cells.
  • cytostatic agents used in chemotherapy are categorized according to their mechanisms of action in the classes of alkylating agents, antimetabolites, mitotic inhibitors, topoisomerase inhibitors and cytostatic antibiotics.
  • the alkylating agents represent a numerically significant, structurally very diverse class of extremely reactive substances. After an optionally preceding activation of the medicament, the active ingredient reacts as an electropophile, in particular with nucleic acids to form covalent bonds. As a result, cross-linking of the DNA, abnormal base pairing or strand breaks occur that prevent replication and eventually lead to cell death.
  • Typical examples of alkylating agents are cyclophosphamide but also cisplatin.
  • a group of particularly effective alkylating agents include the natural antibiotic CC-1065, duocarmycins, yatakemycin, as well as derivatives and analogues of this class of natural products.
  • Chemotherapy for malignant disease is today associated with severe neoplasms. as differentiation between healthy and malignant tissue occurs only through the increased proliferation rate of cancer cells. Therefore, new concepts have been developed which exploit genotypic and phenotypic properties of tumor cells and enable a targeted activation of reversible detoxified prodrug directly at the site of action. Such a targeted activation can be done, for example, by a changed pH, for example a pH reduction. Another possibility is the so-called ADEPT concept (Antibody-Directed Enzyme Prodrug Therapy). This antibody-enzyme conjugates are used, which causes a direct conversion of the non-toxic prodrug into the drug directly at the tumor and achieve high selectivity. This binary therapy approach consists of two steps.
  • a certain amount of antibody-enzyme conjugate is applied, which is then distributed through the bloodstream throughout the organism.
  • the conjugate binds to specific antigens on tumor cell surfaces or is degraded or excreted by the body. If the unbound antibody-enzyme conjugate can no longer be detected, the application of the prodrug takes place in the second step.
  • the possibly non-toxic prodrug is likewise distributed throughout the organism and, due to the enzyme, which is ideally present only on the tumor surface in the form of the antibody-enzyme conjugate, is specifically toxified in the tumor tissue.
  • the released drug then unfolds its toxic effect upon penetration through the cell membrane, while the enzyme remains active on the outside of the tumor cell and can activate further prodrug molecules.
  • ICso Value toxin concentration at which cell growth is suppressed by 50%
  • conjugates of drugs and tumor-specific ligands can be used for selective targeting in cancer therapy. After selective binding of the ligand to a receptor on the tumor surface, internalization of the conjugate and, subsequently, intracellular release occur.
  • CC-1065 For analogues of the antibiotic CC-1065 and the duocarmycines various attempts have been made to achieve the above-mentioned goal.
  • the CC-1065 itself has an IC 50 value of 20 pmol, but in animal try to delay lethal hepatotoxicity and is therefore not suitable for clinical applications. Therefore, attempts have been made to present analogs of this compound.
  • the DNA binding moiety was changed, but also the pharmacophore itself was modified in various forms.
  • seco and prodrug compounds have been synthesized which generally have similar toxicity and selectivities as the spirocyclopropyl compounds, eg CC-1065 or duocarmycins.
  • CC-1065 analogues were described which reversibly give an excellent cytotoxicity result by glycosidation of the detoxified anti-methyl-seco-CBI-DMAI- ⁇ -D-galactoside (+) - (1S, 1 OR) compound and achieve the quotients of the cytotoxicity of the prodrug and the prodrug in the presence of the activated enzyme. QICso values of over 4500 were achieved.
  • Bifunctional alkylating agents are those with two reactive centers. They have the ability to cause intra- or interstrand cross-links of the DNA. With regard to the interstrand cross-linking, particularly good damage to the cells and thus cell death are achieved. These compounds have a high cytotoxicity. Bifunctional derivatives of e.g. Pyrrole benzodiazidepines are described in the literature.
  • a radiation treatment (“beam”, eg radiotherapy with gamma radiation or radioactive isotopes) is indicated, in an advanced stage, in which metastases have already formed
  • beam eg radiotherapy with gamma radiation or radioactive isotopes
  • chemotherapy is usually carried out promptly, and new therapeutic approaches such as treatment with angiogenesis inhibitors and kinase inhibitors, as well as immune and hormone therapy have been introduced.
  • Classic antineoplastic chemotherapy is usually associated with severe side effects.
  • As part of a chemotherapy drugs are administered, which can be distributed through the bloodstream in the peripheral system and so can reach almost all cells.
  • Chemotherapeutics either act cytostatically on human cells, i.e. they prevent cell growth, or cytotoxic, that is, they cause cell death.
  • the cytostatics currently used in cancer therapy are classified according to their targets in the cell cycle in the classes of alkylating agents, antimetabolites, mitotic inhibitors, topoisomerase inhibitors and cytostatic antibiotics.
  • the structurally very diverse class of alkylating agents acts primarily phase-unspecific. Frequently, the drugs in the body are first activated to undergo carbocation before they react with N, O or S nucleophiles in proteins or, in particular, nucleic acids and form covalent bonds. As a consequence, crosslinks of the DNA strands (cross links), abnormal base pairings or strand breaks occur, which impede replication and thus cell division and ultimately lead to cell death.
  • cyclophosphamide (1) which is converted into the actual active ingredient 2 only through biotransformations in the body (poisoning) and is therefore called a prodrug (FIG. 1 a).
  • Platinum complexes with cisplatin (3) (FIG. 1 a) as well-known representatives ter belong to the class of alkylating agents and act primarily by intra- or interstrand cross-links of DNA.
  • the natural antibiotic CC-1065, duocarmycins, yatakemycin, as well as derivatives and analogues of this class of natural products are also classed as particularly effective alkylating agents.
  • Antimetabolites are structural analogues of the body's own metabolite components, which, as antagonists, displace the actual metabolites. They act phase-specifically preferentially in the S-phase of the cell cycle and inhibit important enzymes or lead to the emergence of nonfunctional macro-molecules.
  • a prominent example is the folic acid antagonist methotrexate (4), which as the wrong substrate inhibits dihydrofolate reductase and thereby prevents the formation of tetrahydrofolic acid ( Figure 1 b). This is again u.a. essential for purine synthesis and thus for cell proliferation.
  • Mitosis inhibitors also called spindle toxins enter into the mitosis phase of the cell cycle by binding to the ß-unit of the tubulin dimer and thereby either the structure of the nuclear spindles (eg colchicine, vinca alkaloids such as vincristine (6) and vinblastine (7), ( 1 b) or their degradation (taxol, epothionon).
  • the nuclear spindles eg colchicine, vinca alkaloids such as vincristine (6) and vinblastine (7), ( 1 b) or their degradation (taxol, epothionon).
  • cytostatics consists of inhibitors of topoisomerases I and II. Topoisomerases are assigned the task of unwinding, interrupting and then resealing the twisted strands during DNA replication. If these enzymes are inhibited, they can no longer dissociate from the DNA, causing strand breaks and eventually causing cell death. Typical representatives of this class of substances are etoposide, irinotecan and derivatives of the alkaloid camptothecin (8) (FIG. 1 c).
  • the cytostatic antibiotics include, first and foremost, the anthracyclines daunorubicin (9) and doxorubicin (10) isolated from Streptomyces species (FIG. 1 c), which preferentially act in the S phase of the cell cycle. They intercalate into DNA, interfering with DNA and RNA synthesis. Furthermore, they can induce strand breaks by radical formation and inhibition of topoisomerase II.
  • the clinical benefit in the treatment of cancer has been significantly increased by the use of chemotherapeutic agents, especially in cases of surgically difficult to reach neoplasias or metastases.
  • chemotherapy in addition to the sometimes severe acute side effects that may require a discontinuation of therapy, often brings long-term consequences. These include the induction of secondary tumors, damage to the bone marrow, pulmonary fibrosis or immune deficiencies.
  • a further problem is the development of resistance of tumors to individual cytostatic agents or classes, which occurs due to the natural selection of resistant cells during treatment.
  • Immunotherapy has become the fourth and most recent pillar of cancer treatment.
  • cytokines or antibodies which have immunomodulating or direct antiproliferative properties.
  • a key role is played by the characteristic cell surfaces of the different cell types.
  • glycocalyx On the extracellular side of each cell membrane is the glycocalyx, which consists of glycolipids, glycoproteins and glycosaminoglycans and serves, inter alia, for cell recognition, communication and signal acquisition. Certain components of the glycocalyx function here as antigens which - presented on the surface - are specific for cancer cells (specific antigens) or are over-expressed in tumor cells in comparison to healthy cells (tumor-associated antigens). These antigens represent the central starting point of an immunotherapy: Monoclonal antibodies can selectively bind to the antigens, thus selectively marking the cancer cells and then destroy itself or as a conjugate malignant degeneration.
  • FIG. 2 shows a few examples of the immunotherapy of malignant tumors.
  • cytokines eg interleukin-2, IL-2
  • IL-2 interleukin-2
  • antibodies can be linked to T lymphocytes, causing direct cytolysis of the tumor cell (B).
  • the fusion of cancer cells with antigen-presenting cells is another approach to mobilizing the body's own immune system to destroy neoplasms.
  • the resulting hybrids express more tumor-associated antigens on their surface and thus activate cytotoxic lymphocytes (CTL), which - stimulated by the tumor antigen-presenting hybrids - eliminate cancer cells with identical antigens.
  • CTL cytotoxic lymphocytes
  • DZ dendritic cells
  • C DNA
  • ADC antibody-drug conjugate
  • antibody-enzyme conjugates are used, which convert reversibly detoxified drugs (prodrugs) selectively at the cancer cell into cytotoxic drugs (D).
  • radioimmunotherapy which couples antibodies to radioactive isotopes ( 131 l, 90 Y), exists (F).
  • This approach is used not only in tumor therapy, but also in diagnostics, where it enables, among other things, the localization of metastases.
  • Significant problems with the development of antibody-drug conjugates on the one hand are the cytotoxicity of the toxin and the systemic toxicity of the conjugate, which is often too low.
  • One approach pursued is the use of relatively non-toxic prodrugs of the highly toxic duocarmycin which release the toxin after being taken up into the cell.
  • the work is based on the dimeric duocarmycin analogues developed by the present inventors, in which two CBI units are linked to dicarboxylic acids via a diamide bond.
  • Such compounds have an IC50 of up to 150 fmol and thus constitute the cytotoxic compounds known.
  • these compounds are not suitable to bind a monoclonal antibody, since they have no corresponding functionalities.
  • dimeric duocarmycins have been proposed, which can be linked to a monoclonal antibody via a linker.
  • these compounds all have high systemic toxicity and are in no way superior to the known ADC.
  • ADCs Antibody Drug Conjugates
  • the general problem in the treatment of malignant tumors is that the available chemotherapeutic agents have only a relatively small therapeutic window and therefore there are massive side effects.
  • ADCs are suitable in which usually a cytotoxic small molecule is linked to a monoclonal antibody which binds to tumor-associated antigens. This makes it possible via a so-called targeting the toxin selectively infiltrate into a cancer cell without attacking normal cells.
  • certain conditions must be met for good efficacy and tolerability.
  • it is necessary for the toxin to have a high IC 50 value of ⁇ 1 nmol, but the conjugate with the antibody has only a low toxicity. This is not guaranteed in many cases.
  • the monoclonal antibody used should also not be attached to the Epithelium of normal cells bind. Further difficulties lie in the choice of linker, which on the one hand needs to be stable enough that the toxin is not released in the serum, but is labile enough that it is cleaved off in the cell after endocytosis of the conjugate. Another problem lies in the reduction of the cytotoxicity of the toxin used by introducing functionalities that allow a connection to the monoclonal antibody. In one of the most promising ADCs of the first generation with a doxorubicin as toxin and a Lewis Y antibody, the problem can be understood very well.
  • Adcetris and Kadcyla are further substances with calicheamicin, MMAE, DM1 and DM4 as toxins in the clinical trial.
  • Substances that contain a duo-carmycin or a related compound are not included.
  • conjugates with bifunctional duocarmycin analogs are disclosed. However, these compounds show only moderate activity; this is presumably due to the high toxicity of the conjugate and the comparatively low cytotoxicity of the toxin used, which has lost its effectiveness as a result of the derivatization carried out.
  • WO2007089149 discloses conjugates with monofunctional duocarmycin analogs. Compared to the bifunctional analogs, these compounds have the disadvantage of lower cytotoxicity.
  • WO 2015/1 10935 A1 discloses a multiplicity of bifunctional cytotoxic describe xic means. These include CPI prodrugs and CBI prodrugs.
  • the object of the present invention is to provide novel compounds suitable for the preparation of conjugates with, for example, antibodies, in order to control the compounds in the form of prodrugs to the corresponding therapeutic targets, for example the target cells.
  • chemotherapeutic drugs and prodrugs that will target them to the target areas, such as the target cells.
  • new compounds which represent bifunctional alkylating agents in particular for use in a selective tumor therapy.
  • the novel compounds described herein are characterized by the fact that these new dimers are more cytotoxic than the monomeric prodrugs or drugs.
  • the IC 50 value of the compounds according to the invention is in the pmol range.
  • a much larger QICso value is achieved. That is, the quotient between cytotoxicity of the drug and the cytotoxicity of the prodrug is much greater.
  • a better therapeutic effectiveness associated with a lower cytotoxicity of the prodrug and thus lower side effects in applications in patients can be achieved.
  • a and B are formed independently of each other from the structure I.
  • Hal is a halide selected from F, Cl, Br, I;
  • R is H or an optionally substituted C 1 -C 4 -alkyl group, an optionally substituted C 1 -C 4 -alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted C 1 -C 4 -alkylcarboxy-C 1 -C 4 -alkyl group, halo, CN, a optionally subsitutechnisch Ci - C4 alkylsulfanyl group, an optionally substituted Arylsulfanyl distr, an NR group Z as defined below;
  • Ri is H or a Ci - C4 alkyl group or a Ci - C4 alkoxy group
  • Xi is O, S, N R5, wherein R5 is selected from H and optionally substituted Ci - C4 alkyl;
  • R2 is selected from hydrogen or a cleavable substrate, in particular a cleavable by chemical reaction substrate;
  • G is independently absent, hydrogen or a functional group, in particular selected from an alkyne group, an amino group, a hydroxyl group, a thiol group, a carboxyl group, an azide group or a polyglycine group, wherein G is present as a functional group at least once in the compound ALB ;
  • L is a linking group to the covalent bond of A and B, where L has the structure Z-Y-Z ';
  • each Rz is independently selected from hydrogen and optionally substituted Ci - C4 alkyl or optionally substituted C1 - C4 acyl;
  • Y is selected from a structure according to structure II I or structure IV; Structure II I
  • each RA is independently selected from hydrogen or optionally substituted C1 - C4 alkyl or optionally substituted C1 - C4 acyl;
  • o and p are independently selected from an integer of 1 to 20; where o and p can take the same value or a different value.
  • G is as defined above;
  • X 2 is i) N or S or ii) an aryl or heteroaryl group, wherein (CRA) O and (CRA) P are arranged in metaposition on this aryl group or on this heteroaryl group,
  • R3 is selected from C1 - C10 alkyl such as C1 - C4 alkyl; Co - C4 alkylaryl Co - C10 alkyl group such as Co - C4 alkylaryl Co - C4 alkyl group; Co - C4 Alkylhe- teroaryl Co - C10 alkyl group, such as Co - C4 alkylheteroaryl Co - C4 alkyl group; or a cleavable substrate, in particular a cleavable by chemical reaction substrate; or is not present;
  • R4 is i) absent or a C1 - C10 alkyl group, such as a C1 - C4 alkyl group; a Co - C4 alkylarylCo - C10 alkyl group such as Co - C4 alkylarylCo - C4 alkyl group; a Co - C4 alkylheteroaryl Co - C10 alkyl group, such as Co - C4 alkylheteroaryl Co - C4 alkyl group; or a cleavable substrate, in particular a chemical cleavable substrate, when X 2 is N or S, or ii) R 4 is a C 1 -C 10 alkyl group, such as a C 1 -C 4 alkyl group; or a cleavable substrate, in particular a cleavable by chemical reaction substrate; or is absent if X2 is an aryl or heteroaryl group;
  • glycosidic prodrugs of dimeric duocarmycin are used, which in themselves have only low toxicity, and whose activity after ingestion into the cell is developed by elimination of the sugar component.
  • cleavable linkers wherein a cleavage can be carried out, for example, via an acid-catalyzed hydrolysis, an enzymatic transformation or a glutathione-induced cleavage of disulfides.
  • Acid labile linkers can contain hydrazone, acetal, enol ether, and azomethine functions.
  • compounds containing sugar components or the dipeptide valine-citrulline which can be cleaved by cathepsin B, which is strongly expressed intracellularly are suitable.
  • Disulfide linkers are based on the finding that glutathione occurs intracellularly in much higher concentrations than extracellularly.
  • the attachment of antibodies according to the invention to the linker can be effected via the addition of a lysine-Nh group or a cysteine-SH group to a maleimidocaproyl, a maleimidomethylcyclohexanecarboxylate, a maleimidodioxacaproyl function or comparable functionalities. Further connections can be made by linking two amino functionalities with diethyl squarate and comparable functionalities to form a diamide. The addition of nucleophiles to ⁇ , ⁇ -unsaturated carbonyl compounds has also been used.
  • Another linkage method is the 1, 3-dipolar cycloaddition of linkers with an alkyne or an azide group with antibodies that carry an azide or an alkyne group.
  • an enzymatically induced linkage of polyglycine-substituted toxins or precursors thereof (prodrug) with the aid of a sortase to an antibody can also take place.
  • R 2 , R 3 and / or R 4 is selected from a substrate which is obtained by enzymatic cleavage, such as by proteolytic, oxidative or reductive enzymes, plasmin, cathepsin, cathepsin B, beta-glucuronidase, galactosidase, mannosidase, glucosidase, neuramidase , Saccharosidase, maltase, fructosidase, glycosylases, prostate-specific antigen (PSA), urokinase-type plasminogen activator (u-PA), metalloproteinase, cytochrome P450, or an enzyme targeted by enzyme-directed prodrug therapy how ADEPT, VDEPT, MDEPT, GDEPT, or PDEPT can be split; or a substituent which can be split off or transformed under hypoxic conditions or by reduction by nitroreductase, in particular R2, R3 and / or R4
  • the term "functional group” is understood herein to mean a substituent which can undergo a further structure, the target structure, in particular proteins, in particular antibodies or antibody fragments, a preferably covalent compound in order to bind the compounds according to the invention to these target structures in particular to prepare antibody-compound conjugates according to the invention.
  • cleavable substrate or "cleavable substrate”, as used herein, is understood to mean a structure, such as the target structure, which, under appropriate conditions and / or using appropriate molecules, cleaves off the prodrug and ultimately the active drug becomes. As stated, a corresponding cleavage can be effected physically or chemically, in particular enzymatically.
  • Antibody fragments also include aptamers, lectins, biological modifiers of an answer, enzymes, vitamins, growth factors, steroids, nutrients, sugar residues, oligosaccharide residues, hormones and derivatives, and combinations thereof.
  • antibody is understood here to mean a naturally occurring or recombinant antibody but also antibody fragments, in one embodiment the antibodies are humanized antibodies or antibody fragments. if appropriate, these antibodies or antibody fragments are modified in such a way that binding to the compounds according to the invention can take place via the functional group described herein.
  • the antibodies are directed to tumor-associated antigens or other cell surface components of the target structures so that target-directed delivery of the prodrugs into the cells can occur.
  • antibody-conjugate conjugate is understood here to mean a conjugate of antibody and compound according to the invention, in which case the compound is, for example, a prodrug or drug molecule
  • This conjugate is a form of a target-structure-compound conjugate, eg with the above-mentioned target structures and the compounds according to the invention.
  • the linkage of the compound according to the invention with the antibody takes place via the functional group G in order to covalently connect the antibody according to the invention, including antibody fragments, to the compound according to the invention. If necessary, this covalent bond can be redissolved by suitable means.
  • an embodiment relates to a compound wherein R2 is independently a hydrogen or CH3.
  • a compound is one wherein Hai is Cl and R1 is H.
  • One embodiment relates to a compound, wherein L is a compound according to the structure II, Structure II
  • an embodiment of the present invention is one having a compound wherein X 2 is an aryl group, especially a benzyl group, Y is a structure IV wherein R 4 is a C 1 -C 4 alkyl group, and G is a functional group defined herein.
  • one embodiment is a compound wherein the functional group G is present only on the radical R2.
  • the compounds of the invention showed in vitro experiments excellent cytotoxicity values with IC50 values in the pmol range, partially below the pmol range. Furthermore, the compounds showed an excellent quotient of the IC50.
  • the QICso value of the tested compounds was over 1 000, especially suitable compounds showed values above 1 00 000.
  • the compounds presented herein which are new dimeric prodrugs and drugs of CC-1065 analogues, have a very high cytotoxicity as a drug, while the prodrugs show less cytotoxicity. Thus, these compounds should be much safer in therapeutic use.
  • the compounds of diamines according to the invention are furthermore substantially more cytotoxic than the monomeric prodrugs or drugs. The compounds are thus characterized by a high efficacy with fewer side effects in the application.
  • the compounds according to the invention are distinguished by the fact that they exhibit cytotoxicity values in the pmol range and have a very large quotient of the IC 50 values of the drug to the prodrug.
  • alkyl refers to straight-chained or branched, saturated or unsaturated hydrocarbon substituents, examples of the alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, decyl, isopropyl, sec Butyl, isobutyl, tert-butyl, isopentyl, vinyl, allyl, 1-butenyl, 2-butenyl, isobutenyl, pentenyl and the like.
  • cycloalkyl or “carbon cycles” as used herein refers to saturated or unsaturated, non-aromatic hydrocarbon cycles which may consist of one, two or more rings. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexonyl, etc.
  • heteroalkyl refers to straight-chained or branched, saturated or unsaturated hydrocarbon substituents in which at least one carbon has been replaced by a heteroatom
  • the heteroatoms are preferably selected from S, N, O. , and P.
  • aryl refers to aromatic substituents which may consist of one or more fused rings, and examples of aryl include phenyl, naphthyl and antracenyl.
  • heteroaryl refers to aromatic substituents which may consist of one or more fused rings, wherein at least one carbon atom of the aromatic ring group is replaced by a heteroatom.
  • Ryl groups include pyridinyl, furanyl, pyrrolyl, triazolyl, pyrazolyl, imidazolyl, thiophenyl, indolyl, benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzisoxazolyl, and quinolinyl.
  • heterocycloalkyl or “heterocycles” as used herein refers to saturated or unsaturated, non-aromatic cyclic hydrocarbon substituents which may consist of one or more fused rings, with at least one carbon in one replaced by a heteroatom.
  • heterocycloalkyls include: tetrahydrofuranyl, pyrrolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl, oxyzolidinyl, decahydroquinolinyl.
  • R2, R3 and / or R 4 and conjugated through G antibodies the compounds can be incorporated easily and directed into cells.
  • R2, R3 and / or R 4 is preferably hydrogen.
  • R 2, R 3 and / or R 4 represents a substrate which can be cleaved enzymatically, for example, to convert prodrugs which have a cleavable product on the substituent R 2, R 3 and / or R 4 into drugs.
  • the substrate R2, R3 and / or R 4 is a cleavable product.
  • a cleavage can be done by chemical reaction, for example due to a change in environmental conditions, such as pH, concentration of certain ions, etc.
  • the substrate R2, R3 and / or R 4 is a cleavable substrate.
  • This cleavable substrate is preferably one obtained by proteolytic enzymes, plasmin, cathepsin, cathepsin B, beta-glucuronidase, galactosidase, mannosidase, glucosidase, neuramidase, sucrose, maltase, fructosidase, glycosylases, prostate specific antigen (PSA), urokinase type Plasminogen activator (u-PA), metalloproteinase, or an enzyme that can be specifically cleaved using targeted enzyme prodrug therapy, such as ADEPT, VDEPT, MDEPT, GDEPT, or PDEPT; or a substituent which can be cleaved or transformed under hypoxic conditions or by reduction by nitroreductase.
  • proteolytic enzymes plasmin, cathepsin, cathepsin B, beta-glucuronidase, galactosidase, mannosidase, glucos
  • the radical R 2, R 3 and / or R 4 is preferably one selected from the group comprising monosaccharide, disaccharide or oligosaccharide, in particular hexoses, pentoses or heptoses, optionally as the deoxy derivative or amino derivative and optionally substituted by halogen, C 1 -8 alkyl, C1-8 acyl, C1-8 heteroalkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C4-12 aryl or C4-12 heteroaryl, amino or amide groups, or with amino, amido or carboxy moieties which may optionally be substituted with halogen, C 1-8 alkyl, C 1-8 acyl, C 1-8 heteroalkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 4-12 aryl or C 4-12 heteroaryl, amino or amide radicals; Dextran, dipeptide, tripeptide, tetrapeptide, oligopeptide,
  • labile substituents can be used under certain environmental conditions, such as hemiacetals and acetals, benzyl groups and substituted benzyl groups.
  • a targeting of the compounds according to the invention to target structures may be possible. That is, a targeted coupling of the compounds according to the invention to target structures for targeting these conjugates, for example into the target cells or target tissue, is possible, and a corresponding introduction of these compounds according to the invention into, for example, selected cells and cell types is possible.
  • the split off or the transformation of the compound of the invention with R2, R3 and / or R4 other than H may be carried out by chemical, photochemical, physical, biological or enzymatic processes under the appropriate conditions.
  • the substrate is suitably accessible to known methods such as ADEPT (Antibody Directed Enzyme Prodrug Therapy), PDEPT (Polymer Directed Enzyme Prodrug Therapy) or MDEPT (Macromolecular-Directed Enzyme Prodrug Therapy), VDEPT (Virus-Directed Enzyme Prodrug Therapy) or GDEPT ( Gene-Directed Enzyme Prodrug Therapy).
  • ADEPT Antibody Directed Enzyme Prodrug Therapy
  • PDEPT Polymer Directed Enzyme Prodrug Therapy
  • MDEPT Macromolecular-Directed Enzyme Prodrug Therapy
  • VDEPT Virus-Directed Enzyme Prodrug Therapy
  • GDEPT Gene-Directed Enzyme Prodrug Therapy
  • Another aspect of the present invention is directed to an antibody-conjugate conjugate wherein an antibody via the functional group G is linked to the compound of the invention as defined above.
  • the conjugate is one wherein the antibody is directed against a tumor antigen or an antigen that is expressed on a target structure, such as a cell.
  • the antibody-compound conjugate is one wherein the antibody is one of an antibody, an antibody fragment such as F (ab ') 2, F (ab'), Fab, Fv, sFv, scFv.
  • the present application is directed to pharmaceutical compositions containing the compounds of the invention, optionally with pharmaceutically acceptable carriers or diluents.
  • the compounds according to the invention can be present in the form of pharmaceutically acceptable salts or solvates. That is, the pharmaceutical composition contains a compound of the present invention or an antibody-compound conjugate of the present invention.
  • salts are in particular acid addition salts which are formed correspondingly to amine groups. Likewise, base addition salts are possible or corresponding zwitter addition salts.
  • pharmaceutically acceptable solvates refers to the association of one or more solvent molecules and a inventive compound.
  • solvent molecules which form pharmaceutically acceptable solvates include water, isopropyl alcohol, ethanol, methanol, DSMO, ethyl acetate and acetic acid.
  • the compounds of the invention are particularly suitable for the preparation of pharmaceutical compositions suitable in tumor therapy.
  • Monomers of the bifunctional compounds of the invention are known as cytotoxic compounds suitable for tumor therapy.
  • the present invention includes pharmaceutical compositions which contain the compounds according to the invention in addition to the customary carriers or diluents.
  • the preparation of the pharmaceutical preparations listed above is carried out in a conventional manner by known methods, e.g. by mixing the agent or excipients.
  • the compounds according to the invention can be administered in total amounts of 0.5 to about 500, preferably 1 to 150 mg / kg of body weight per 24 hours, optionally in the form of several single doses, to obtain the desired results.
  • the person skilled in the art knows the possibilities for determining the dose amount. This can be done depending on the age, the body weight, the type and severity of the disease of the patient, the type of preparation and the application of the drug and the period or the interval of administration.
  • the seco-duocarmycin derivatives described herein carry, for example, alkyne, carboxyl, amino, azide, thiol and hydroxy groups, ie functional groups G, which can be easily linked to antibodies using the methods discussed above.
  • FIG. 1 A typical approach of many possible for the attachment of an antibody to the bifunctional seco-duocarmycin analogs is shown in FIG. The presented method even includes the possibility of inserting two different antibodies and thus of addressing different tumor-associated antigens.
  • the compounds can be very efficiently detoxified by glycosidation with values of about 6,000 for the monofunctional or about 1,000,000 for the bifunctional compounds. Such a procedure is very difficult with other toxins.
  • compound 1 has a slightly increased IC 50 value of 60 pM.
  • a cleavable linker of known type, functionalized benzene-1,3-diacetates can be used.
  • the chains may additionally contain one or two oxygen atoms, one or two nitrogen atoms with an alkyl or aryl group or one or two sulfur atoms ,
  • bifunctional CBI derivatives for example with an N atom in the chain connecting the two CBI units, can also be used for insertion of moieties. noclonal antibodies are used
  • n is an integer from 0 to 1 o and o and p is an integer from 0 to 5, in the chains () 0 and () P can additionally one or two oxygen atoms, one or two Stickstoffatonne with an alkyl or aryl group or contain one or two sulfur atoms.
  • All compounds can e.g. be detoxified by benzylation or glycosidation of the phenolic hydroxyl groups.
  • the release of the toxin then occurs in the lysosome by oxidative cleavage with P 450 or by reaction with a glycohydrolase: b) attachment of a monoclonal antibody via the benzene ring of a benzyl-protected bifunctional duocarmycin derivative.
  • the compounds are stable in serum and the conjugates show very low toxicity.
  • r may be an integer of 0-5, the radical () r may further contain one or two oxygen atoms, one or two sulfur atoms or one or two NRz groups, wherein Rz is as defined above.
  • the group () r may be a group Y as defined above.
  • dicarboxylic acid components In order to have the possibility of binding the dimeric duocarmycin derivatives, dicarboxylic acid components have been developed that carry functionality in the center.
  • the functionality may be an alkyne group, an amino group, an OH group, an SH group or a polyglycine group. Numerous methods are known for linking such functionalities to monoclonal antibodies.
  • R can be an alkyl having 0 to 5 atoms, halogen, OH, CO to C5 alkoxy, N-C0 to C5 alkyl and / or S-C0 to C5 alkyl and / or S-aryl.
  • the described compounds and antibody-compound conjugates can be used in order to introduce the prodrugs into the target cells or the target tissue in order to treat a tumor treatment or precursors thereof.
  • the tumors include in particular solid tumors.
  • FIGS. 3 and 4 show the synthesis of a precursor of bifunctional seco-CBI glycosides. Shown is the formation of the acetals on the sugar and formation of a triazole group for the protection of the azide group, wherein the azide group is suitable later to form a corresponding antibody-conjugate conjugate with the antibody.
  • FIGS. 6 and 7 show the examples of structures according to the invention and their in vitro cytotoxicity in human bronchial carcinoma cells of the A549 line.
  • FIG. 5 shows a suitable structure of an antibody compound
  • This compound represents an example of suitable linking of the compound according to the invention via a cleavable substrate with an antibody.
  • multiplicities of the first order were designated as: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), etc.
  • Higher order signals were referred to as m (multiplet).
  • IR spectroscopy IR spectrums were recorded using Bruker vector 22 spectrometer, UV spectroscopy: UV spectrums were recorded using JASCO V-630 spectrometer, mass spectrometry: ESI-MS and ESI-HRMS spectra were recorded using Bruker Daltonics Apex IV.
  • Tetrakis (triphenylphosphine) palladium (O) ((6 mg, 5 ⁇ mol, 5 mol%), copper iodide ( 2 mg, 10 ⁇ , 10 mol%), and then ethynyl trimethylsilane (22 ⁇ , 1 58 ⁇ mol, 1 .5 eq.) was added at room temperature, and stirring was continued for 16 hours at the same temperature. Evaporation of the solvent under high pressure gave the crude product, which was then purified by flash chromatography (EtOAcPE 2: 3 to EtOAc: PE 3: 2) to give 55 (61 mg, 88%).
  • Figures 8 to 14 show the in vitro cytotoxicity of the above-mentioned synthesized compounds in human bronchial carcinoma cells of the A549 line. The effectiveness of the exemplary compounds can be clearly seen, the IC 50 values are shown accordingly.

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