US20160354482A1 - Pharmaceutical compositions comprising macrolide diastereomers, methods of their synthesis and therapeutic uses - Google Patents

Pharmaceutical compositions comprising macrolide diastereomers, methods of their synthesis and therapeutic uses Download PDF

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US20160354482A1
US20160354482A1 US14/913,965 US201414913965A US2016354482A1 US 20160354482 A1 US20160354482 A1 US 20160354482A1 US 201414913965 A US201414913965 A US 201414913965A US 2016354482 A1 US2016354482 A1 US 2016354482A1
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formula
composition
compound
diastereomer
antibody
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Thomas Nittoli
Nareshkumar F. Jain
Thomas Patrick MARKOTAN
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Regeneron Pharmaceuticals Inc
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Regeneron Pharmaceuticals Inc
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Assigned to REGENERON PHARMACEUTICALS, INC. reassignment REGENERON PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: JAIN, NARESHKUMAR F., MARKOTAN, Thomas Patrick, NITTOLI, THOMAS
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    • A61K47/48384—
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A61K47/48569—
    • 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
    • A61K47/6801—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
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
    • 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
    • A61K47/6851—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 the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • Proliferative diseases are characterized by uncontrolled growth and spread of abnormal cells. If the spread of these cells is not controlled, it can result in death.
  • Proliferative diseases for example cancer, can be treated by surgery, radiation, chemotherapy, hormone-based therapy and/or immunotherapy. A number of these treatments, particularly the chemotherapy, are based on the use of anti-proliferative drugs which limit the spread of the abnormal cells.
  • Anti-proliferative drugs typically are indiscriminate in their ability to kill cells, affecting both normal and abnormal cells based simply on whether a cell is replicating. Regardless, most anti-proliferative drugs require a relatively high concentration at the locale of the abnormal cell proliferation to be effective. It is this combination of providing sufficient anti-proliferative drug at a site of abnormal cell growth without also causing significant death to normal cells systemically or in the vicinity of these cells that this disclosure addresses.
  • conjugates of tumor targeted probes such as antibodies or growth factors
  • toxins such as pseudomonas or diphtheria toxins.
  • Conjugates for use in the treatment of cancer thereby target the anti-proliferative drug to a population of abnormal cells.
  • conjugates that include the toxin maytansine have been employed for the treatment of cancer. Maytansine has shown great effectiveness as an anti-proliferative agent but the compound's toxicity has proven problematic toward normal cells.
  • anti-proliferative compounds exhibit asymmetric structures, such as the Maytansinoid family of macrolides, and may therefore exist in the form of a racemic mixture, in the form of separate enantiomers with configuration “R” and “S”, or (+) and ( ⁇ ), per stereogenic center, and various diastereomers.
  • the present disclosure shows that targeted delivery of a single maytansinoid diastereomer exhibits improved inhibitory cell proliferation profile as compared to delivery of its respective mixture of diastereomers. Therefore, diastereomers in accordance with embodiments described herein can be used to prepare medicinal products with improved therapeutic profile that can be useful for the treatment of specific diseases and conditions, particularly cancer.
  • compositions comprising a plurality of drug molecules for formula (I):
  • compositions comprising a plurality of drug molecules of formula I, wherein n is 1, and R 1 and R 2 are each independently hydrogen.
  • composition comprising a plurality of drug molecules of formula I are present in the composition in a diastereomeric excess of about 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more.
  • the drug molecules of formula I are present in the composition in a diastereomeric excess of from about 90% to about 100%, or from about 95% to about 100%, or from about 98% to about 100%.
  • composition comprising a plurality of drug molecules of formula I wherein one of the at least two diastereomers is characterized by a 1 H NMR spectra of FIG. 1 .
  • the term “about”, when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%.
  • the expression “about 100” includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
  • compositions comprising a plurality of drug molecules of formula I wherein the drug molecules are present in the composition in a diastereomeric excess of greater than 50% and show greater anti-proliferative activity than a corresponding composition comprising drug molecules of formula I that are not present in a diastereomeric excess of greater than 50%.
  • compositions comprising a plurality of drug molecules of formula I further comprising a therapeutically effective amount of a second or additional agent including, for example, a chemotherapeutic agent, an anti-inflammatory agent, an antibiotic, and the like.
  • compositions comprising a plurality of drug molecules of formula I represented by the following structure:
  • one of the at least two diastereomers is a compound of formula (i)
  • one of the at least two diastereomers is a compound of formula (ii)
  • the present disclosure also provides a compound of formula (i) or (ii),
  • compositions comprising a plurality of ligand-drug conjugates of formula (II):
  • compositions comprising a plurality of ligand-drug conjugates of formula II, wherein n is 1, and R 1 and R 2 are each independently hydrogen.
  • compositions comprising a plurality of ligand-drug conjugates of formula II are present in the composition in a diastereomeric excess of about 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more.
  • the drug molecules of formula II are present in the composition in a diastereomeric excess of from about 90% to about 100%, or from about 95% to about 100%, or from about 98% to about 100%.
  • compositions comprising a plurality of ligand-drug conjugates of formula II in the compositions in a diastereomeric excess of greater than 50% and show greater antiproliferative activity than a corresponding composition comprising ligand-drug conjugates of formula II that are not present in a diastereomeric excess of more than 50%.
  • compositions comprising a plurality of ligand-drug conjugates of formula II, wherein the ligand is an antibody or antigen-binding fragment thereof.
  • the antibody or antigen-binding fragment thereof can be developed to specifically bind a tumor-associated antigen.
  • the n can be 1, and R 1 and R 2 can each be independently a hydrogen.
  • the disclosure provides compositions comprising a plurality of ligand-drug conjugates of formula II, wherein the ligand is an antibody, or antigen-binding fragment thereof which specifically binds a tumor-associated antigen, and the ligand-drug conjugates are present in the composition in a diastereomeric excess of more than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more.
  • compositions comprising a plurality of ligand-drug conjugates of formula II, wherein the antibody, or antigen-binding fragment thereof specifically binds a tumor-associated antigen and further wherein the tumor-associated antigen is selected from the group consisting of AFP, ALK, BAGE proteins, ⁇ -catenin, brc-abl, BRCA1, BORIS, CA9, carbonic anhydrase IX, caspase-8, CD20, CD40, CDK4, CEA, CLEC12A, cMET, CTLA4, cyclin-B1, CYP1B1, EGFR, EGFRvIII, ErbB2/Her2, ErbB3, ErbB4, ETV6-AML, EphA2, Fra-1, FOLR1, GAGE proteins (e.g., GAGE-1, -2), GD2, GD3, GloboH, glypican-3, GM3, gp100, Her2, HLA/B-raf, HLA/k-ras
  • the antibody, or antigen-binding fragment have amino acid sequences that vary from the above-mentioned antibodies but that retain the ability to bind a given tumor-associated antigen.
  • Such variant antibodies and antibody fragments can comprise one or more additions, deletions, or substitutions of amino acids when compared to parent sequence, but exhibit biological activity that is essentially equivalent to that of the described antibodies.
  • Two conjugates are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose under similar experimental conditions, either single dose or multiple dose.
  • Some conjugates will be considered equivalents or pharmaceutical alternatives if they are equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on, e.g., chronic use, and are considered medically insignificant for the particular drug product studied.
  • two conjugates are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.
  • two conjugates are bioequivalent if a patient can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects, including a clinically significant change in immunogenicity, or diminished effectiveness, as compared to continued therapy without such switching.
  • two conjugates are bioequivalent if they both act by a common mechanism or mechanisms of action for the condition or conditions of use, to the extent that such mechanisms are known.
  • Bioequivalence may be demonstrated by in vivo and in vitro methods.
  • Bioequivalence measures include, e.g., (a) an in vivo test in humans or other mammals, in which the concentration of the conjugate or its metabolites is measured in blood, plasma, serum, or other biological fluid as a function of time; (b) an in vitro test that has been correlated with and is reasonably predictive of human in vivo bioavailability data; (c) an in vivo test in humans or other mammals in which the appropriate acute pharmacological effect of the conjugate (or its target) is measured as a function of time; and (d) in a well-controlled clinical trial that establishes safety, efficacy, or bioavailability or bioequivalence of a conjugate.
  • the present disclosure also provides a novel method for preparation of a composition comprising a plurality of drug molecules of formula (I):
  • the disclosure provides a method for preparing composition comprising a plurality of drug molecules of formula I, wherein the method further comprises step (d), further wherein step (d) comprises purifying the compound of formula I obtained in step (c) as explained above.
  • the disclosure provides a method for preparing compositions comprising a plurality of drug molecules of formula I, wherein the solid substrate is selected from the group consisting of silica gel, celite, alumina, a zeolite, and crushed molecular sieves.
  • the solid substrate is selected from the group consisting of silica gel, celite, alumina, a zeolite, and crushed molecular sieves.
  • Other like solid substrates may also be utilized as long as the solid substrate allows for proper positioning of the macrolide III to allow stereoselective addition of maleimide IV.
  • the disclosure provides a method for preparing compositions comprising a plurality of drug molecules of formula I, wherein n is 1, and R 1 and R 2 are each independently hydrogen.
  • the disclosure provides a method for preparing compositions comprising a plurality of drug molecules of formula I, wherein the organic solvent comprises a polar aprotic solvent such as DMF, DMA, HMPT, NMP, acetonitrile, dioxane, acetone, DMSO, THF, ethyl acetate, methyl acetate, methylene chloride, propylene carbonate or mixtures thereof.
  • a polar aprotic solvent such as DMF, DMA, HMPT, NMP, acetonitrile, dioxane, acetone, DMSO, THF, ethyl acetate, methyl acetate, methylene chloride, propylene carbonate or mixtures thereof.
  • the disclosure provides a method for preparing compositions comprising a plurality of drug molecules of formula I, wherein the polar aprotic solvent comprises acetonitrile.
  • the disclosure provides a method for preparing compositions comprising a plurality of drug molecules of formula I, wherein the organic solvent and the water are present in ratio of from about 1:1 to about 4:1 or from about 1:1 to about 10:1.
  • the disclosure provides a method for preparing compositions comprising a plurality of drug molecules of formula I, wherein the molar ratio of the starting material having formula III and the compound of formula IV is from about 1:1 to about 1:3.
  • the disclosure provides a method for preparing compositions comprising a plurality of drug molecules of formula I, further comprising combining the compound of formula I with an antibody or antigen-binding fragment thereof to make an antibody-drug conjugate.
  • the disclosure provides a method for preparing compositions comprising a plurality of drug molecules of formula I, wherein the compound of formula I is attached to the antibody or antigen-binding fragment via an S, O, or NR 3 .
  • the disclosure provides a method for preparing a composition comprising a plurality of drug molecules of formula I, wherein the drug molecules of formula I are present in the composition in a diastereomeric excess of about 60% 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more.
  • compositions comprising a plurality of drug molecules of formula I represented by the following structure:
  • compositions of the present invention in a diastereoselective excess of greater than 50%.
  • chromatographic separation of a racemic mixture or mixture of diastereomers e.g., HPLC on normal, reverse, or chiral stationary phase using polar aprotic solvent mixtures, etc.
  • compositions wherein a plurality of the drug molecules of formula I, or the ligand-drug conjugates of formula II, are contained within the compositions in a therapeutically effective amount, and further comprising a pharmaceutically acceptable diluent, carrier or excipient.
  • compositions comprising a plurality of drug molecules of formula II further comprising a therapeutically effective amount of a second chemotherapeutic agent.
  • compositions comprise a compound of formula (I) and/or (II) of the present disclosure which may be administered in combination with one or more additional compounds or therapies.
  • Co-administration and combination therapy are not limited to simultaneous administration, separately or together, but also include sequential administrations.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a composition comprising one or more compounds of formula (I) and/or (II) and one or more other therapeutic agents; as well as administration of a composition comprising compound of formula (I) and/or (II) of the present disclosure and one or more additional agent(s) in its own separate pharmaceutical dosage formulation.
  • a composition comprising a compound of formula (I) and/or (II) and, a cytotoxic agent, a chemotherapeutic agent, or a growth inhibitory agent can be administered to the patient together in a single dosage composition such as a combined formulation, or each agent can be administered in a separate dosage formulation.
  • a composition comprising a compound of formula (I) and/or (II) and one or more additional agents can be administered concurrently, or separately at staggered times, i.e., sequentially.
  • Non-limiting examples of such additional therapeutic agents include cytokine inhibitors (e.g., an interleukin-1 (IL-1) inhibitor (such as rilonacept or anakinra, a small molecule IL-1 antagonist, or an anti-IL-1 antibody); IL-18 inhibitor (such as a small molecule IL-18 antagonist or an anti-IL-18 antibody); IL-4 inhibitor (such as a small molecule IL-4 antagonist, an anti-IL-4 antibody or an anti-IL-4 receptor antibody); IL-6 inhibitor (such as a small molecule IL-6 antagonist, an anti-IL-6 antibody or an anti-IL-6 receptor antibody); aspirin; NSAIDs; steroids (e.g., prednisone, methotrexate, etc.); low dose cyclosporine A; tumor necrosis factor (TNF) or TNF receptor inhibitors (e.g., a small molecule TNF or TNFR antagonist or an anti-TNF or TNFR antibody); uric acid synthesis inhibitors (e.g.,
  • the additional therapeutic agent(s) may be administered prior to, concurrent with, or after the administration of the one or more compounds of formula (I) and/or (II) (for purposes of the present disclosure, such administration regimens are considered the administration of one or more compounds of formula (I) and/or (II) “in combination with” a therapeutic agent).
  • cytotoxic agent refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells.
  • the term is intended to include radioactive isotopes (e.g., I 131 , I 125 , Y 90 and Re 186 ), chemotherapeutic agents, and toxins such as enzymatically active toxins of bacterial, fungal, plant or animal origin, or fragments thereof.
  • chemotherapeutic agent is a chemical compound useful in the treatment of cancer.
  • examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofos
  • anti-hormonal agents that act to regulate or inhibit hormone action on tumors
  • anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • a “growth inhibitory agent” when used herein refers to a compound or composition which inhibits growth of a cell, especially a cancer cell either in vitro or in vivo.
  • growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce G1 arrest and M-phase arrest.
  • Classical M-phase blockers include the vincas (vincristine and vinblastine), TAXOL®, and topo II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin.
  • DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C.
  • compositions comprise a therapeutically effective amount of an active agent and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable means approved by a regulatory agency of the United States Federal or State government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
  • the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection.
  • a solubilizing agent such as lidocaine to ease pain at the site of the injection.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the active agents of the disclosure can be formulated as neutral or salt forms.
  • Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
  • the amount of the active agent of the disclosure which will be effective in the treatment of a medical condition, can be determined by standard clinical techniques based on the present description.
  • in vitro assays may optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the condition, and should be decided according to the judgment of the practitioner and each subject's circumstances.
  • suitable dosage ranges for intravenous administration are generally about 0.5 to 20 milligrams of active compound per kilogram body weight.
  • Suitable dosage ranges for intranasal administration are generally about 0.01 pg/kg body weight to 1 mg/kg body weight.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the disclosure provides a method of treatment of a medical disorder in an individual suffering from the medical disorder comprising administering to the individual an effective amount of a composition comprising a compound of formula (I) and/or (II), and further comprising administering sequentially or consecutively an additional therapy or administering at least one additional therapeutic agent.
  • the disclosure relates to a method of treating a disease sensitive to treatment with said method, said method comprising parenterally administering to a patient in need thereof a therapeutically effective dose of the composition comprising a compound of formula (I) and/or (II).
  • compositions comprising compounds of formula (I), formula (II), formula (i), formula (ii), or a combination thereof and/or pharmaceutical formulations thereof in the manufacture of a medicament for the treatment, prevention and/or amelioration of a medical disorder.
  • compositions comprising compounds of formula (I), formula (II), formula (i), formula (ii), or a combination thereof and/or pharmaceutical formulations thereof in the manufacture of a medicament for the treatment, prevention and/or amelioration of a tumor.
  • compositions herein can also be useful in the treatment of a medical disorder selected from autoimmune diseases and other immunological diseases and dysfunctions, inflammatory diseases, infectious diseases, neurodegenerative diseases, bone disorders, and cardiovascular diseases. Further, any disorder that can benefit from the targeted delivery of a toxic substance to particular cells, cell types, tissues and/or organs is within the scope of the present invention.
  • compositions comprising mixtures of compounds as represented by formula (I) and formula (II).
  • conjugate refers to compound having a Ligand, linker and Biologically Active Molecule.
  • Illustrative examples include compounds of formula (II).
  • spacer refers to chemical building blocks of the linker used to spatially separate the Ligand from the Biologically Active Molecule and to allow for catabolism of the linker inside of cells.
  • macrolide refers to any Biologically Active Molecule having a macrolide ring.
  • alkyl refers to a hydrocarbon radical having a straight or branched chain or combinations thereof.
  • Alkyl radicals can be a univalent, a bivalent or a cyclic radical. Examples of univalent alkyl radicals are methyl, ethyl, 1-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like.
  • bivalent alkyl radicals include
  • cyclic alkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Typical alkyl radicals have from one to ten carbon atoms, one to nine carbon atoms, one to eight carbon atoms, one to seven carbon atoms, one to six carbon atoms, one to five carbon atoms, one to four carbon atoms, one to three carbon atoms, one to two carbon atoms or one carbon atom.
  • Typical cycloalkyl are 3 to 7 member monocyclic ring radicals.
  • pharmaceutically acceptable salt refers to both organic and inorganic salts of the conjugate compounds described herein, e.g., compounds of formula (I), and (II).
  • the salts are pharmaceutically acceptable and include: sulfate, citrate, nitrate, phosphate, ascorbate, bromide, gluconate, benzoate, oxalate, pantothenate, and the like.
  • pharmaceutically acceptable salts herein may include more than one charged atom in its structure as well as one or more counter ion. Preparation of conjugate compounds herein as pharmaceutically acceptable salts is well known to one of skill in the art.
  • ligand as used herein means any molecule or compound that specifically or selectively interacts with and/or binds to a second molecule or compound.
  • a ligand is an antibody or antigen-binding fragment thereof.
  • Other examples of ligands suitable for use in the context of the present invention include, e.g., aptamers, peptides that specifically interact with a particular antigen (e.g., peptibodies), receptor molecules, and antigen-binding scaffolds (e.g., DARPins, HEAT repeat proteins, ARM repeat proteins, tetratricopeptide repeat proteins, and other scaffolds based on naturally occurring repeat proteins, etc., [see, e.g., Boersma and Pluckthun, 2011 , Curr. Opin. Biotechnol. 22:849-857, and references cited therein]).
  • Antibodies exist as intact immunoglobulins, or as a number of well-characterized fragments produced by digestion with various peptidases. For example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)′ 2 , a dimer of Fab which itself is a light chain joined to V H -C H by a disulfide bond.
  • the F(ab)′ 2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)′ 2 dimer into an Fab′ monomer.
  • the Fab′ monomer is essentially Fab with part of the hinge region.
  • antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology.
  • antibody also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv (scFv) single variable domains (Dabs)) or those identified using display libraries such as phage, E. coli or yeast display libraries (see, for example, McCafferty et al. (1990) Nature 348:552-554).
  • scFv single chain Fv
  • Dabs single variable domains
  • human antibody as used herein is intended to include antibodies having variable and constant regions derived from human immunoglobulin sequences.
  • the human mAbs of the invention may include amino acid residues not encoded by human immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3.
  • the term “human antibody”, as used herein, is not intended to include mAbs in which CDR sequences derived from the germline of another mammalian species have been grafted onto human FR sequences.
  • terapéuticaally effective amount refers to an amount that produces the desired effect for which it is administered. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).
  • racemate as used herein means an equimolar mixture of a pair of enantiomers.
  • racemate also refers to a racemic mixture.
  • enantiomer refers to compounds which non-superimposable with the mirror images of each other. Enantiomers may exist in either the (R) or (S) configuration.
  • stereoselective synthesis refers to a chemical reaction that leads to formation of a single stereoisomer or an enantiomer-enriched mixture of isomers from among two or more possible stereoisomers.
  • diastereomeric excess refers to the difference between the mole fraction of the desired single diastereomer as compared to the remaining diastereomers in a composition. Diastereomeric excess is calculated as follows:
  • stereomerically pure refers to a compound wherein the indicated stereoisomer is present to a greater extent than other stereoisomers of that compound, e.g., the compound is present in diastereomeric excess.
  • the stereomerically pure compounds described herein comprise 80% or greater, 85% or greater, 90% or greater, 95% or greater, or 97% or greater by weight of one stereoisomer of the compound.
  • Conjugates in accordance with various embodiments described herein can be prepared by any known method in the art.
  • An illustrative protocol for producing conjugates is provided in the Examples below.
  • the conjugates can be prepared by i) reacting a Ligand with drug molecules of formula (I) to form a conjugate of formula (II), and ii) purifying the conjugate.
  • the conjugates are prepared by reacting a Ligand, linker and biologically active macrolide in a single reaction. Once the conjugates in accordance with the invention are prepared they can be purified.
  • compositions comprising drug molecules of formula (I) and/or compositions comprising conjugate compounds of formula (II) described herein can be evaluated for their ability to suppress proliferation of various cancer cell lines in vitro.
  • compositions comprising drug molecules or formula (I) and/or compositions comprising conjugate compounds of formula (II) can be applied to in vitro plated cancer cells for a predetermined number of days and surviving cells measured in assays by known methods.
  • FIG. 1 illustrates an 1 H-NMR spectrum of Maytansin-3-N-methyl-L-alanine-propanamidyl-3-thio-3-succinimidyl-N-methylcyclohexyl-4-trans-carboxysuccinate (5).
  • the 1 H-NMR spectrum is consistent with a single diastereomer present in at least 95% diastereomeric excess since the spectrum is not complicated by resonances attributable to the other diastereomer.
  • Example 2 sets forth the 1 H-NMR spectrum of the mixture of diastereomers).
  • FIG. 2 illustrates an 1 H-NMR spectrum of mixture of diastereomers of Maytansin-3-N-methyl-L-alanine-propanamidyl-3-thio-3-succinimidyl-N-methylcyclohexyl-4-trans-carboxysuccinate (6).
  • FIG. 3 illustrates that in SKBR3 cells the single diastereomer compound conjugate HER2-5 (in vitro and in vivo lots) possessed an IC50 value of 0.3 nM versus 0.9 nM for the mixture of diastereomer conjugate HER2-6.
  • FIG. 4 illustrates that in BT474 cells the single diastereomer compound conjugate HER2-5 (in vitro) in possessed an IC 50 value of 4.6 nM while the HER2-5 (in vivo) lot had an IC 50 value of 4.0 nM versus 11.6 nM for the mixture of diastereomer conjugate HER2-6.
  • FIG. 5 illustrates that in NCI-N87 cells the single diastereomer compound conjugate HER2-5 (in vitro) possessed an IC 50 value of 0.6 nM while the HER2-5 (in vivo) lot had an IC 50 value of 0.4 nM versus 1.0 nM for the mixture of diastereomer conjugate HER2-6.
  • FIG. 6 illustrates that in HEK293/hEGFRvIII cells the single diastereomer compound conjugate EGFRvIII-5 possessed an IC 50 value of 0.4 nM while the mixture of diastereomer conjugate EGFRvIII-6 had an IC 50 value of 0.5 nM.
  • FIG. 7 illustrates that in MMT/hEGFRvIII cells the single diastereomer compound conjugate EGFRvIII-5 possessed an IC 50 value of 0.5 nM while the mixture of diastereomer conjugate EGFRvIII-6 had an IC 50 value almost 20 fold higher at 9.8 nM.
  • FIG. 8 illustrates that in U251/hEGFRvIII cells the single diastereomer compound conjugate EGFRvIII-5 possessed an IC 50 value of 2.4 nM while the mixture of diastereomer conjugate EGFRvIII-6 had an IC 50 value of 3.3 nM.
  • FIG. 9 illustrates that in Ovcar-3 cells the single diastereomer compound conjugate MUC16-5 possessed an IC 50 value of 6.3 nM while the mixture of diastereomer conjugate MUC16-6 had an IC 50 value of 16.0 nM.
  • FIG. 10 illustrates that in PC3/MUC16long cells the single diastereomer compound conjugate MUC16-5 in possessed an IC 50 value of 0.34 nM while the mixture of diastereomer conjugate MUC16-6 had an IC 50 value at 0.80 nM.
  • FIG. 11 illustrates tumor growth curves in mice following dosing with HER2-5 and control reagents.
  • Mice received PBS vehicle ( ⁇ ), 300 ug/kg DM1-SMe ( ⁇ ) and Isotype Control mAb at 15 mg/kg ( ⁇ ).
  • Mice also received HER2 mAb ( ⁇ ), HER2-5 ( ⁇ ) and Isotype Control-5 ( ⁇ ) at doses of 1 mg/kg (A), 5 mg/kg (B) and 15 mg/kg (C).
  • Mice received 3 once weekly doses of conjugates and control agents as indicated by the black arrows (T. Groups are N 8, Mean ⁇ SE.).
  • FIG. 13 illustrates percentage change in animal weights following dosing with HER2-5 and control reagents.
  • Mice received PBS vehicle ( ⁇ ), 300 ug/kg DM1-SMe ( ⁇ ) and Isotype Control mAb at 15 mg/kg ( ⁇ ).
  • Mice also received HER2 mAb ( ⁇ ), HER2-5 ( ⁇ ) and Isotype Control-5 ( ⁇ ) at doses of 1 mg/kg (A), 5 mg/kg (B) and 15 mg/kg (C).
  • Mice received 3 once weekly doses of conjugates and control agents as indicated by the black arrows (T. Groups are N 8, Mean ⁇ SE.).
  • Proton NMR spectra (for compounds that could not be detected by UV) were acquired on a Varian Inova 300 MHz instrument, while mass spectra were collected on an Agilent 1100 series LC/MSD with electrospray ionization source and quadrupole ion trap analyzer. All conjugates were analyzed using a Bruker ultraFleXtreme MALDI-TOF-TOF mass spectrometer. All starting materials and solvents were purchased commercially and used without purification, unless otherwise noted.
  • the maleamic acid from Step A (36.8 g, 144 mmol) and sodium acetate (13.6 g, 165 mmol) were dissolved in acetic anhydride (368 mL), sealed in a glass reaction vessel, and heated to 120° C. for 3 hours.
  • the cooled reaction mixture (a black syrup) was poured onto water (3 L), stirred, and extracted with dichloromethane.
  • the organic layer was dried over Na 2 SO 4 , filtered over a sintered glass funnel, and the clear filtrate evaporated and dried under high vacuum giving the title compound as a yellow solid (7.00 g, 20%).
  • step B The product of the preceding step B (10.0 g, 42.1 mmol) was dissolved in dichloromethane (50 mL) under Ar, treated with N-hydroxysuccinimide (7.27 g, 63.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC, 12.4 g, 64.5 mmol), and the reaction was stirred at ambient temperature overnight. The resulting brown solution was diluted with dichloromethane, washed with water and brine, dried over Na 2 SO 4 , filtered over a sintered glass funnel, and the filtrate concentrated and dried in vacuo.
  • EDAC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • DM1 The title compound, known in the art as DM1, was prepared using a modified version of the method described by Whitesides et al. ( J. Org. Chem., 1991, 56, 2648-2650). Maytansin-3-N-methyl-L-Ala-(3-methyldisulfanyl) propanamide (DM1-SMe, 2.42 g, 3.09 mmol, prepared in a manner similar to Ho and Carrozzella, U.S. Pat. Appl.
  • 2007/0037972 A1 was dissolved in acetonitrile (30 mL), treated with a solution of tris(2-carboxyethyl)phosphine hydrochloride (8.23 g, 28.7 mmol) in water (30 mL), the pH was raised to ca. 3 with the addition of saturated aqueous NaHCO 3 (5 mL), the flask was purged with Ar, and the reaction was stirred at ambient temperature under a rubber septum (vented due to effervescence). After 2 h, the reaction was treated with brine (ca. 100 mL), bubbled with Ar for 5 minutes (to remove the free methylmercaptan), and the phases separated.
  • Compound 5 comprises predominantly a single diastereomer of the linker-DM1 cytotoxic compound, whereas Compound 6 comprises a mixture of various linker-DM1 diastereomers.
  • the antibodies used in this Example were an anti-HER2 antibody having variable regions derived from humAb4D5-8 from Carter et al, PNAS 1992 89 4285, an anti-EGFRvIII antibody having variable regions derived from clone 131 from WO2013075048 A1, and an anti-MUC16 antibody having variable regions derived from clone 3A5 from WO2007001851.
  • the antibodies were expressed in CHO cells and purified by Protein A.
  • a non-binding isotype control antibody derived from an infectious disease antigen having no relation to oncology was also used in this Example.
  • the antibodies (10 mg/ml) in 50 mM HEPES, 150 mM NaCl, pH 8.0, and 10% (v/v) DMA were conjugated with a 6 fold excess of compound 5 or 6 for 1 hour at ambient temperature.
  • the conjugates were purified by size exclusion chromatography and sterile filtered. Protein and linker payload concentrations were determined by UV spectral analysis and MALDI-TOF mass spectrometry. Size-exclusion HPLC established that all conjugates used were >95% monomeric, and RP-HPLC established that there was ⁇ 0.5% unconjugated linker payload. Yields are reported in Table 1 based on protein. All conjugated antibodies were analyzed by UV for linker payload loading values according to Hamblett et al, Cancer Res 2004 10 7063 and by mass difference, native versus conjugated. The results are summarized in Table 1.
  • Cells were seeded in PDL-coated 96 well plates at 10,000 (SK-BR-3 and NCI-N87), 15,000 (BT-474), 3000 (Ovcar-3 and PC3/Muc16), 2000 (HEK293/hEGFRvIII), 1500 (U251/hEGFRvIII), or 400 (MMT/hEGFRvIII) cells per well in complete growth media and grown overnight.
  • serially diluted antibody-drug conjugates or free payload were added to the cells at final concentrations ranging from 1 ⁇ M to 1 pM and incubated for 3 days. Each concentration was run in duplicate and reported with the respective standard deviation.
  • the single diastereomer compound conjugate HER2-5 in vitro
  • the HER2-5 (in vivo) lot had an IC 50 value of 4.0 nM versus 11.6 nM for the mixture of diastereomer compound conjugate HER2-6 (Table 2, FIG. 4 ).
  • the naked HER2 antibody had little anti-proliferation activity.
  • the single diastereomer compound conjugate HER2-5 in vitro
  • the HER2-5 (in vivo) lot had an IC 50 value of 0.4 nM versus 1.0 nM for the mixture of diasteromer compound conjugate HER2-6 (Table 2, FIG. 5 ).
  • the naked HER2 antibody had little anti-proliferation activity.
  • the single diastereomer compound conjugate EGFRvIII-5 possessed an IC 50 value of 0.5 nM while the mixture of diastereomer compound conjugate EGFRvIII-6 had an IC 50 value of 9.8 nM (Table 2, FIG. 7 ).
  • the naked EGFRvIII antibody had little anti-proliferation activity.
  • the single diastereomer compound conjugate MUC16-5 possessed an IC 50 value of 6.3 nM while the mixture of diasteroemer compound conjugate MUC16-6 had an IC 50 value of 16.0 nM (Table 4, FIG. 8 ).
  • the naked Muc16 antibody had little anti-proliferation activity.
  • DM1-SMe maytansin-3-N-methyl-L-Ala-(3-methyldisulfanyl) propanamide
  • mice bearing HER2+ gastric cancer xenografts were assessed for efficacy.
  • 5 ⁇ 10 6 NCI-N87 cells (ATCC CRL-5822) were implanted subcutaneously into the lower right flank of CB-17 SCID mice (Taconic). Once tumors had reached an average volume of 150 mm 3 , mice were randomized in to groups of eight and dosed with HER2-5 or control reagents.
  • Control reagents included PBS vehicle, free DM1-SMe, isotype control, isotype control-5, or HER2. Mice received once weekly doses for three weeks and tumor volumes and body weights were monitored twice weekly throughout the study. Conjugates were dosed at 1, 5 and 15 mg/kg, as these doses had been shown to be effective in previous in vivo studies by Lewis-Phillips et al (Lewis-Phillips G et al., Can Res 2008).
  • HER2-5 demonstrated clear anti-tumor efficacy, with doses of 5 and 15 mg/kg leading to significant decreases in initial tumor volume and eradication of some tumors at the higher dose ( FIGS. 11 and 12 ). A significant delay in tumor growth relative to control agents was also observed in the 1 mg/kg dose level. No adverse events were observed following dosing, with mice receiving HER2-5 demonstrating robust weight gain throughout the study ( FIG. 13 ).

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